CN110214135B

CN110214135B - Indanyl amino pyrazinyl cyclopropane carboxylic acid, pharmaceutical composition and application thereof

Info

Publication number: CN110214135B
Application number: CN201880007924.0A
Authority: CN
Inventors: M·埃克哈特; H·瓦格纳; S·彼得斯
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 2017-01-26
Filing date: 2018-01-22
Publication date: 2023-02-21
Anticipated expiration: 2038-01-22
Also published as: JP2020505394A; US10253004B2; US20180208560A1; EP3573965B1; AR110777A1; EP3573965A1; TW201840541A; JP6968181B2; CN110214135A; WO2018138026A1

Abstract

The invention relates to compounds of formula (I), wherein the radical R, R ¹ 、R ² 、R ³ M and n are as defined in claim 1, which have valuable pharmacological properties, in particular binding to and modulating the activity of the GPR40 receptor. The compounds are useful in the treatment and prevention of diseases which may be affected by the receptor, such as metabolic diseases, especially type 2 diabetes. Furthermore, the present invention relates to novel intermediates which facilitate the synthesis of compounds of formula (I).

Description

Indanyl amino pyrazinyl cyclopropane carboxylic acid, pharmaceutical composition and application thereof

Technical Field

The present invention relates to novel indanyl aminopyrazinyl cyclopropanecarboxylic acids which are agonists of G-protein coupled receptor 40 (GPR 40, also known as free fatty acid receptor FFAR 1); to processes for their preparation; to intermediates for their preparation; to pharmaceutical compositions comprising these compounds; and to their medical use for the prophylaxis and/or treatment of diseases which may be affected by the modulation of GPR40 function. In particular, the pharmaceutical compositions of the invention are suitable for the prevention and/or treatment of metabolic diseases, such as diabetes, more particularly type 2 diabetes, and conditions associated with the disease, including insulin resistance, obesity, cardiovascular disease and dyslipidemia.

Background

Metabolic diseases are diseases caused by abnormal metabolic processes, which may be congenital diseases caused by genetic enzyme abnormalities, and acquired diseases caused by diseases of endocrine organs or failure of metabolically important organs (such as liver or pancreas).

Diabetes is a disease state or process derived from multiple causes and is defined as chronic hyperglycemia associated with organ damage and dysfunction of metabolic processes. Different types of diabetes can be distinguished according to their etiology, which results from an absolute deficiency of insulin (a deficiency or reduction in insulin secretion) or a relative deficiency of insulin. Type I diabetes (IDDM, insulin dependent diabetes) typically occurs in young adults under the age of 20. It is postulated to have an autoimmune etiology, triggering insulitis, followed by destruction of the beta cells of the Langerhans islets responsible for insulin synthesis. Furthermore, in latent autoimmune Diabetes in adults (LADA; diabetes Care.8:1460-1467, 2001), beta cells are destroyed by autoimmune attack. The amount of insulin produced by the remaining islet cells is too low, resulting in elevated blood glucose levels (hyperglycemia). Type II diabetes usually occurs at a higher age. It is primarily associated with insulin resistance in the liver and skeletal muscle, but also with defects in the langerhans islets. High blood glucose levels (as well as high blood lipid levels) in turn lead to impaired beta cell function and increased beta cell apoptosis.

Persistent or poorly controlled hyperglycemia is associated with a wide range of pathologies. Diabetes is a very disabling disease because the antidiabetic drugs commonly found today do not control blood glucose levels well to completely prevent the occurrence of high and low blood glucose levels. Blood glucose levels outside of these ranges are toxic and cause long-term complications such as retinopathy, nephropathy, neuropathy and peripheral vascular disease. There are many associated conditions such as obesity, hypertension, stroke, heart disease and hyperlipidemia, and the diabetic population is at substantial risk.

Obesity is associated with an increased risk of subsequent diseases, such as cardiovascular disease, hypertension, diabetes, hyperlipidemia and increased mortality. Diabetes (insulin resistance) and obesity are part of the "metabolic syndrome" defined as the link between several diseases (also known as syndrome X, insulin resistance syndrome or the severe quartet (deadly quartz)). These usually occur in the same patient and are the major risk factors for the development of type II diabetes and cardiovascular disease. It has been suggested that the control of blood lipid levels and blood glucose levels is required for the treatment of type II Diabetes, heart disease and other emerging metabolic syndromes (see, e.g., diabetes 48, 1836-1841,1999, jama 288.

The free fatty acid receptor GPR40 (also known as FFAR, FFAR1 or FFA 1) is a member of the cell surface receptor and G-protein coupled receptor gene superfamily, which was first identified as a so-called orphan receptor, i.e. a receptor without a known ligand, based on the predicted presence of seven putative transmembrane regions in the corresponding protein (Sawzdargo et al, (1997) biochem. Biophysis. Res. Commun.239: 543-547). GPR40 has been found to be highly expressed in several specific cell types: pancreatic beta cells and insulin-secreting cell lines, as well as in enteroendocrine cells, taste cells, and reportedly in immune cells, splenocytes, and the human brain and monkey brain expression. Meanwhile, fatty acids of different chain lengths are believed to represent endogenous ligands of GPR40, the activation of which is mainly associated with the regulation of the Gq family of intracellular signaling G-proteins and the concomitant induction of elevated calcium levels, although the activation of Gs-and Gi-proteins has also been reported to regulate intracellular cAMP levels. GPR40 is activated inter alia by long chain FFA, in particular oleate, and the PPAR-gamma agonist rosiglitazone.

Fatty acids used as GPR40 activators have been recognized to increase blood glucose elevation-induced insulin secretion via the GPR40 receptor expressed in insulin secreting cells (Itoh et al, (2003) Nature 422 (2003) j. Biol. Chem.278:11303-11311 kotarsky et al (2003) biochem. Biophysis. Res. Commu.301: 406-410. Despite initial controversy, the use of GPR40 agonists appears to be suitable for increasing insulin release for the treatment of Diabetes (see, e.g., diabetes 2008,57,2211 j.med.chem.2007,50, 2807. Generally, the treatment of long-term diabetes leads to a gradual decrease in islet activity, and therefore, type 2 diabetic patients need daily insulin injection treatment instead after long-term treatment. GPR40 agonists may have the potential to restore or maintain islet function, and therefore GPR40 agonists may also be beneficial because they may delay or prevent the attenuation and loss of islet function in type 2 diabetic patients.

It is well recognized that incretins GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide; also known as gastric inhibitory peptide) stimulate insulin secretion and are rapidly inactivated in vivo by DPP-4. These peptidyl hormones are secreted by endocrine cells located in the epithelial cells of the small intestine. When these endocrine cells sense an increase in glucose concentration in the lumen of the digestive tract, they can act as triggers for incretin release. When an increase in blood glucose caused by the digestion of a meal is expected, incretins are transmitted to the beta cells in the pancreas through the circulation and cause the beta cells to secrete more insulin. Further studies demonstrating the regulatory role of GPR40 for the release of incretins from enteroendocrine cells, including CCK, GLP-1, GIP, PYY, and the like, among others, indicate that GPR40 modulators may also indirectly promote insulin release from islet beta cells, for example, through the synergistic effect of GLP-1 and possibly GIP on insulin release, and that other releases of incretins may also contribute to the overall beneficial contribution of GPR40 modulation to metabolic disorders. The indirect contribution of GPR40 modulation to insulin release, by increasing plasma levels of incretins, may be further enhanced by the concurrent administration of an inhibitor of the enzyme responsible for incretin degradation, such as an inhibitor of DPP-4.

An insulin imbalance leads to conditions such as type II diabetes, which is a serious metabolic disease. Modulation of GPR40 function in the regulation of insulin secretion indicates that therapeutic agents capable of modulating GPR40 function are useful in the treatment of disorders such as diabetes and conditions associated with the disease, including insulin resistance, obesity, cardiovascular disease, and dyslipidemia.

Objects of the invention

It is an object of the present invention to provide novel compounds, described below as compounds of formula I, in particular novel indanylaminopyrazinylcyclopropanecarboxylic acids, which are active on the G-protein coupled receptor GPR40, in particular as agonists of said G-protein coupled receptor GPR40.

It is another object of the present invention to provide novel compounds, in particular novel indanylaminopyrazinylcyclopropanecarboxylic acids, which have an activating effect on the G-protein coupled receptor GPR40 in vitro and/or in vivo and have suitable pharmacological and pharmacokinetic properties to enable their use as medicaments.

It is another object of the present invention to provide potent GPR40 agonists, which are particularly useful for the treatment of metabolic disorders, such as diabetes, dyslipidemia, and/or obesity.

It is another object of the invention to provide methods of treating a disease or condition mediated by activation of the G-protein coupled receptor GPR40 in a patient.

It is another object of the present invention to provide pharmaceutical compositions comprising at least one compound of the present invention.

It is another object of the present invention to provide a combination of at least one compound of the present invention and one or more other therapeutic agents.

Other objects of the present invention will be apparent to those skilled in the art from the above and the following description and examples.

GPR40 modulators are known in the art, for example, compounds disclosed in WO 2004/041266 (EP 1 55422), WO 2007/033002, WO 2009/157418 and WO 2013/178575. The indanyl aminopyrazinyl cyclopropanecarboxylic acids of the present invention can provide several advantages, such as enhanced potency, high metabolic and/or chemical stability, high selectivity and tolerability, enhanced solubility and the possibility of forming stable salts.

Disclosure of Invention

In a first aspect, the present invention relates to compounds of the formula

Wherein

R is selected from the group consisting of R-G1

H、F、Cl、Br、I、C _1-6 Alkyl radical, C _2-6 -alkenyl, C _2-6 -alkynyl, C _3-6 -cycloalkyl, NC-, HNR ^N -C(＝O)-、C _1-4 -alkyl-NR ^N -C(＝O)-、C _3-6 -cycloalkyl-NR ^N -C (= O) -, heterocyclyl-NR ^N -C (= O) -, heteroaryl-NR ^N -C(＝O)-、HOOC-、C _1-4 -alkyl-O-C (= O) -, O ₂ N-、HR ^N N-、C _1-4 -alkyl-R ^N N-、C _1-4 -alkyl-C (= O) NR ^N -、C _3-6 -cycloalkyl-C (= O) NR ^N -, heterocyclyl-C (= O) -NR ^N -, heteroaryl-C (= O) NR ^N -、C _1-4 -alkyl-S (= O) ₂ NR ^N -、C _3-6 -cycloalkyl-S (= O) ₂ NR ^N -, heterocyclyl-S (= O) ₂ NR ^N -, heteroaryl-S (= O) ₂ NR ^N -、HO-、C _1-6 -alkyl-O-, HOOC-C _1-3 -alkyl-O-, heterocyclyl-C _1-3 -alkyl-O-, phenyl-C _1-3 -alkyl-O-, C _3-6 -cycloalkyl-O-, heterocyclyl-O-, heteroaryl-O-, C _1-4 alkyl-S-, C _3-6 -cycloalkyl-S-, heterocyclyl-S-, C _1-4 -alkyl-S (= O) -, C _3-6 -cycloalkyl-S (= O) -, heterocyclyl-S (= O) -, C _1-4 -alkyl-S (= O) ₂ -、C _3-6 -cycloalkyl-S (= O) ₂ -, heterocyclyl-S (= O) ₂ -, phenyl-S (= O) ₂ -, heteroaryl-S (= O) ₂ -、HNR ^N -S(＝O) ₂ -、C _1-4 -alkyl-NR ^N -S(＝O) ₂ -, heterocyclyl, phenyl and heteroaryl,

wherein in the residue groups mentioned for R, each alkyl, cycloalkyl and heterocyclyl group or group is optionally substituted by one or more F atoms and optionally one to three independently selected from Cl, C _1-3 -alkyl, NC-, (R) ^N ) ₂ N-、HO-、C _1-3 -alkyl-O-and C _1-3 -alkyl-S (= O) ₂ -is substituted; and

wherein in the residue groups mentioned for R, each of the phenyl and heteroaryl groups or radicals is optionally substituted by one to five groups independently selected from F, cl, C _1-3 Alkyl, HF ₂ C-、F ₃ C-、NC-、 (R ^N ) ₂ N-、HO-、C _1-3 -alkyl-O-, F ₃ C-O-and C _1-3 -alkyl-S (= O) ₂ -is substituted with a substituent;

wherein in the residue groups mentioned for R, each heterocyclic group or subgroup is selected from

Cyclobutyl of one of which CH ₂ The radical being-NR ^N -or-O-substitution;

C _5-6 -cycloalkyl radical, one of which is CH ₂ The radical being-C (= O) -, -NR ^N -, -O-, -S-or-S (= O) ₂ -substitution and/or substitution of one CH group by N;

C _5-6 -a cycloalkyl group, one of which CH ₂ Radical is-NR ^N -or-O-substitution, second CH ₂ The radical being-NR ^N -, -C (= O) -or-S (= O) ₂ -substitution and/or substitution of one CH group by N; and

C _5-6 -cycloalkyl radicals in which two CH ₂ The radical being-NR ^N -substitution for or of one CH ₂ The radical being-NR ^N -substitution and another substitution by-O-and a third CH ₂ The radical being-C (= O) -or-S (= O) ₂ -substitution and/or substitution of one CH group by N;

wherein in the residue groups mentioned for R, the respective heteroaryl group or group is selected from

Tetrazolyl and five-or six-membered heteroaromatic rings comprising one, two or three each independently selected from = N-, -NR ^N -O-and-S-, wherein in a heteroaryl group comprising-HC = N-units, the units are optionally substituted by-NR ^N -C (= O) -substitution;

wherein in heteroaryl and heterocyclyl rings having one or more NH groups, each of said NH groups is substituted by NR ^N Replacing;

R ¹ selected from group R ¹ G1, the group consisting of H, F, cl, C _1-4 Alkyl radical, C _3-6 -cycloalkyl-, HO-C _1-4 Alkyl radical, C _1-4 -alkyl-O-C _1-4 Alkyl, NC-, HO-, C _1-4 -alkyl-O-, C _3-6 -cycloalkyl-O-, C _1-4 alkyl-S-, C _1-4 -alkyl-S (O) -and C _1-4 -alkyl-S (O) ₂ -a composition of matter,

wherein at R ¹ In the mentioned residue groups, any alkyl and cycloalkyl group or radicals are optionally substituted by one or more F atoms, and where a plurality of R are present if m is 2,3 or 4 ¹ May be the same or different;

m is an integer selected from 1,2, 3 and 4;

R ² selected from H, F, cl, C _1-4 Alkyl, NC-and C _1-4 Group R consisting of alkoxy groups ² -G1，

Wherein at R ² In the residue groups mentioned, any alkyl group or sub-group is optionally substituted by one or more F atoms, and where a plurality of R are present if n is 2 or 3 ² May be the same or different;

R ³ selected from H, F, cl, C _1-4 Alkyl, NC-and C _1-4 -alkyl-O-group R ³ -G1，

Wherein at R ³ In the residue groups mentioned, each alkyl group or sub-group is optionally substituted by one or more F atoms;

n is an integer selected from 1,2 and 3;

R ^N are independently selected from group R ^N G1, group consisting of H, C _1-4 Alkyl radical, HO-C _1-4 -alkyl- (H) ₂ C)-、 C _1-3 -alkyl-O-C _1-4 -alkyl-, C _1-4 -alkyl-C (= O) -, C _1-4 -alkyl-NH-C (= O) -, C _1-4 -alkyl-N (C) _1-4 -alkyl) -C (= O) -, C _1-4 -alkyl-O-C (= O) -and C _1-4 -alkyl-S (= O) ₂ -a composition of matter,

wherein at R ^N In the residue groups mentioned, each alkyl group or subgroup is optionally substituted by one or more F atoms;

wherein in any of the definitions mentioned above, any alkyl or sub-group may be straight-chain or branched, if not otherwise specified,

isomers, tautomers, stereoisomers, metabolites, prodrugs, solvates, hydrates and salts thereof, in particular physiologically acceptable salts thereof with inorganic or organic acids or bases, or combinations thereof.

The extension-Gn used in the definition is intended to identify the genus n of the corresponding substituent. For example, R-G1 defines genus 1 of substituent R.

The expression "optionally substituted by one or more F atoms" means that a F atom may be substituted for zero H atoms connected to the carbon atoms of the corresponding group or subgroup, or for one up to all H atoms, preferably one to five H atoms, or more preferably one to three H atoms may be substituted by a F atom.

Another aspect of the present invention relates to a pharmaceutical composition comprising one or more compounds of general formula I according to the present invention or one or more pharmaceutically acceptable salts thereof, and optionally one or more inert carriers and/or diluents.

In another aspect, the invention relates to a method of treating a disease or condition mediated by activation of the G-protein coupled receptor GPR40 in a patient in need thereof characterized in that a compound of formula I or a pharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the present invention there is provided a method of treating a metabolic disease or disorder (e.g. diabetes, dyslipidemia and/or obesity) in a patient in need thereof, characterized in that a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof is administered to the patient.

According to a further aspect of the invention there is provided the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method of treatment as hereinbefore and hereinafter described.

According to a further aspect of the invention there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in a method of treatment as hereinbefore and hereinafter described.

In another aspect, the invention relates to a method of treating a disease or condition mediated by activation of the G-protein coupled receptor GPR40 in a patient, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more other therapeutic agents.

In another aspect, the invention relates to a combination of a compound of general formula I, or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents for use in the treatment of a disease or condition mediated by the activation of the G-protein coupled receptor GPR40.

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound according to general formula I or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents, and optionally one or more inert carriers and/or diluents.

Other aspects of the invention will be apparent to those skilled in the art from the description and experimental sections set forth above and below.

Detailed Description

Unless otherwise indicated, the groups, residues and substituents, in particular R, R ¹ 、R ² 、R ³ M and n are as defined above and below. If a residue, substituent or group occurs multiple times in a compound, they may have the same or different meanings. Some preferred meanings of the individual radicals and substituents of the compounds according to the invention are given below. Any of these definitions may be combined with each other.

R:

R-G1:

The group R is preferably selected from the group R-G1 as defined above.

R-G2:

In another embodiment, the group R is selected from the group consisting of R-G2

H、F、Cl、C _1-6 Alkyl radical, C _3-6 -cycloalkyl, NC-, HNR ^N -C(＝O)-、C _1-4 -alkyl-NR ^N -C(＝O)-、C _3-6 -cycloalkyl-NR ^N -C (= O) -, heterocyclyl-NR ^N -C(＝O)-、HOOC-、 HR ^N N-、C _1-4 -alkyl-R ^N N-、C _1-4 -alkyl-C (= O) NR ^N -、C _3-6 -cycloalkyl-C (= O) NR ^N -, heterocyclyl-C (= O) NR ^N -、C _1-4 -alkyl-S (= O) ₂ NR ^N -、HO-、C _1-6 -alkyl-O-, HOOC- (C) _1-2 -alkyl) -O-, heterocyclyl-C _1-2 -alkyl-O-, phenyl-C _1-2 -alkyl-O-, C _3-6 -cycloalkyl-O-, heterocyclyl-O-, heteroaryl-O-, C _1-4 -alkyl-S (= O) ₂ -、C _3-6 -cycloalkyl-S (= O) ₂ -, heterocyclyl-S (= O) ₂ -、HNR ^N -S(＝O) ₂ -、C _1-4 -alkyl-NR ^N -S(＝O) ₂ -, heterocyclyl and heteroaryl,

wherein each alkyl, cycloalkyl and heterocyclyl group or group in the residue groups mentioned for R is optionally substituted by one or more F atoms and optionally one to two independently selected from Cl, H ₃ C-、NC-、R ^N HN-、HO-、H ₃ C-O-and H ₃ C-S(＝O) ₂ -is substituted;

wherein each heteroaryl group or subgroup in the residue groups mentioned for R is optionally selected from F, cl, H, via one to three substituents independently selected from ₃ C-、F ₃ C-、NC-、(R ^N ) ₂ N-、HO-、H ₃ C-O-、 F ₃ C-O-and H ₃ C-S(＝O) ₂ -is substituted with a substituent;

wherein each heterocyclic group or sub-group in the residue group mentioned for R is selected from

Cyclobutyl radicalOne of CH of the group ₂ The radical being-NR ^N -or-O-substitution;

C _5-6 -a cycloalkyl group, one of which CH ₂ The radical being-C (= O) -, -NR ^N -, -O-, -S-or-S (= O) ₂ -substitution and/or substitution of one CH group by N;

C _5-6 -cycloalkyl radical, one of which is CH ₂ The radical being-NR ^N -or-O-substitution, second CH ₂ The radical being-NR ^N -, -C (= O) -or-S (= O) ₂ -substitution and/or substitution of one CH group by N;

wherein each heteroaryl group or sub-group in the residue group mentioned for R is selected from

Tetrazolyl, five membered heteroaromatic rings (which contain 1,2 or 3 heteroatoms each independently selected from = N-, -NH-, O and S) and six membered heteroaromatic rings (which contain one or two = N-atoms) wherein the-HC = N-unit is optionally replaced by-NH-C (= O) -;

and wherein in the above heteroaryl and heterocyclyl groups or radicals each containing one or more NH groups, the NH group is replaced by NR ^N And (4) substitution.

R-G3:

In another embodiment, the group R is selected from the group R-G3 consisting of H, F, cl, C _1-4 Alkyl radical, C ₃ Cycloalkyl, NC-, H ₂ N-C(＝O)-、C _1-3 -alkyl-NR ^N -C(＝O)-、HOOC-、 H ₂ N-、C _1-3 -alkyl-C (= O) NR ^N -、C _1-4 -alkyl-S (= O) ₂ NR ^N -、HO-、C _1-5 -alkyl-O-, HOOC-CH ₂ -O-, heterocyclyl-CH ₂ -O-, phenyl-CH ₂ -O-、C _3-6 -cycloalkyl-O-, heterocyclyl-O-, heteroaryl-O-, heterocyclyl-S (= O) ₂ -, heterocyclyl and heteroaryl,

wherein each alkyl, cycloalkyl and heterocyclyl group or group in the residue groups mentioned for R is optionally substituted by one or more F atoms and optionally by one selected from Cl, H ₃ C-、NC-、R ^N HN-、 HO-、H ₃ C-O-and H ₃ C-S(＝O) ₂ Group of (A) to (B)Substitution;

wherein each heteroaryl group or subgroup in the residue groups mentioned for R is optionally selected from F, cl, H, via one to two substituents independently selected from ₃ C-、F ₃ C-、NC-、(R ^N ) ₂ N-、HO-、H ₃ C-O-、F ₃ C-O-and H ₃ C-S(＝O) ₂ -is substituted with a substituent;

wherein each of the heterocyclic groups or radicals in the residue groups mentioned for R is selected from

A cyclobutyl radical in which one CH ₂ The radical being-NR ^N -or-O-substitution;

wherein each heteroaryl group or subgroup in the residue groups mentioned for R is selected from tetrazolyl, five membered heteroaromatic ring (containing 1,2 or 3 heteroatoms each independently selected from = N-, -NH-, O and S) and six membered heteroaromatic ring (containing one or two = N-atoms) wherein the-HC = N-unit is optionally replaced by-NH-C (= O) -;

and wherein in each of the heteroaryl and heterocyclyl groups or radicals mentioned in R which contain one or more NH groups, the NH group is replaced by NR ^N And (4) replacing.

R-G4:

According to another embodiment, the group R is selected from the group R-G4 consisting of:

H、F、Cl、CN-、H ₂ NC(＝O)-、H ₃ CNH-C(＝O)-、(H ₃ C) ₂ N-C(＝O)-、HOOC-、 H ₂ N-；

C _1-3 -an alkyl group optionally substituted with one or more F or optionally mono-substituted with HO-;

cyclopropyl, optionally mono-substituted with NC-;

H ₃ C-O-, optionally via C _1-4 -alkyl, HOOC-, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl or 1,1-dioxotetrahydrothiopyranyl monosubstitution,

wherein the optionally attached to H ₃ C of C-O- _1-4 Alkyl is optionally NC-, HO-or H ₃ C-S(＝O) ₂ -monosubstitution, and

wherein said oxetanyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and 1,1-bis

The oxotetrahydrothiopyranyl group is optionally substituted with H ₃ C-or HO-monosubstitution;

cyclopropyl-O-, tetrahydrofuranyl-O-, tetrahydropyranyl-O-, and benzyl-O-; and

a heteroaryl group selected from pyrazolyl, oxetanyl, thiazolyl, tetrazolyl, pyridyl, pyridin-2-onyl, pyrazinyl, pyrimidinyl and pyridin-4-onyl,

wherein each of said heteroaryl groups is optionally via H ₃ C-or H ₃ C-O-monosubstitution, and

wherein each H-N group in the heteroaryl group is optionally substituted with H ₃ C-N or (H) ₃ C) ₂ C(OH)-H ₂ C-N substitution.

R-G5:

In another embodiment, the group R is selected from the group consisting of R-G5

H、F、Cl、H ₃ C-、H ₃ C-H ₂ C-、(H ₃ C) ₂ CH-、

F ₃ C-、HOCH ₂ -、-CN、 H ₂ N-C(＝O)-、H ₃ C-NH-C(＝O)-、(H ₃ C) ₂ N-C(＝O)-、HOOC-、H ₂ N、H ₃ C-O-, cyclopropyl-O-),

Where the asterisk (—) indicates the connection site/connection point.

R-G6:

In another embodiment, the group R is selected from the group consisting of R-G6

Where the asterisk (—) indicates the connection site/connection point.

¹ R:

R ¹ -G1:

The group R ¹ Preferably selected from group R as defined above ¹ -G1。

R ¹ -G2:

According to one embodiment, the radical R ¹ Selected from H, F, cl, C _1-3 Alkyl, cyclopropyl, NC-, HO-and C _1-3 -alkyl-O-group R ¹ -G2，

Wherein at R ¹ Each alkyl group or sub-group in the residue groups mentioned in (a) is optionally substituted with one or more F atoms.

R ¹ -G3:

According to one embodiment, the radical R ¹ Selected from H, F, cl, H ₃ C-、H ₃ C-H ₂ C-、(H ₃ C) ₂ CH-、 F ₃ C-, CN-and H ₃ C-O-group R ¹ -G3。

R ¹ -G4:

According to one embodiment, the radical R ¹ Is selected from the group consisting of H ₃ C-group R ¹ -G4。

² R:

R ² -G1:

The group R ² Preferably selected from group R as defined above ² -G1。

R ² -G2:

In another embodiment, the group R ² Selected from H, F, cl, H ₃ C-、F ₃ C-, NC-and H ₃ CO-group R ² -G2。

R ² -G3:

In another embodiment, the group R ² R selected from the group consisting of H and F ² -G3。

R ² -G4:

In another embodiment, the group R ² Selected from the group R consisting of H ² -G4。

R ² -G5:

In another embodiment, the group R ² Selected from the group R consisting of F ² -G5。

³ R:

R ³ -G1:

The group R ³ Preferably selected from group R as defined above ³ -G1。

R ³ -G2:

In another embodiment, the group R ³ Is selected from H, H ₃ C-and H ₃ CO-group R ³ -G2。 R ³ -G3:

In another embodiment, the group R ³ Selected from the group R consisting of H ³ -G3。

^N R:

R ^N -G1:

The group R ^N Preferably selected from group R as defined above ^N -G1。

R ^N -G2:

In another embodiment, the group R ^N Is selected from H, C _1-3 Alkyl radical, HO-C _1-4 -alkyl-H ₂ C-、H ₃ C-O-C _1-4 -alkyl-, C _1-3 -alkyl-C (= O) -and C _1-3 -alkyl-S (= O) ₂ Group R of ^N -G2。

R ^N -G3:

In another embodiment, the group R ^N Is selected from H, H ₃ C-、HO-C ₃ -alkyl-H ₂ C-、 H ₃ C-C (= O) -and H ₃ C-S(＝O) ₂ Group R of ^N -G3。

m:

m is an integer selected from 1,2, 3 and 4.

Preferably, m is an integer selected from 1 and 2.

More preferably, m is 2.

n:

n is an integer selected from 1,2 and 3.

Preferably, n is an integer selected from 1 and 2.

More preferably, n is 1.

The following preferred embodiments of the compounds of formula I are described using general formulae i.1, i.2, i.3 and i.4, wherein they encompass any tautomers, solvates, hydrates and salts, in particular pharmaceutically acceptable salts thereof.

Examples of preferred sub-embodiments (E) according to the invention are listed in table 1 below, wherein the individual substituents of the individual embodiments are defined according to the definitions described above, and wherein all other substituents of formulae I, i.1, i.2, i.3 and i.4 are defined according to the definitions described above. For example, entry-G1 in the R-column and in the E1 row indicates that in embodiment E1, the substituent R is selected from the definitions designated as R-G1. The same applies to other variables embedded in the general formula.

Table 1:

another embodiment relates to compounds of formula I, wherein

R is selected from

H、F、Cl、-CN、H ₂ NC(＝O)-、H ₃ CNH-C(＝O)-、(H ₃ C) ₂ N-C(＝O)-、HOOC-、 H ₂ N-；

cyclopropyl, optionally mono-substituted with NC-;

wherein the optionally attached to H ₃ C of C-O- _1-4 -alkyl groups optionally via HO-or H ₃ C-S(＝O) ₂ -monosubstitution, and

wherein the oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl and 1,1-dioxotetrahydrothiopyranyl groups are optionally via H ₃ C-or HO-monosubstitution;

cyclopropyl-O, tetrahydrofuranyl-O-, tetrahydropyranyl-O-, and benzyl-O-; and

a heteroaryl group selected from pyrazolyl,

Oxazolyl, thiazolyl, tetrazolyl, pyridyl, pyridin-2-onyl, pyrazinyl, pyrimidinyl and pyrimidin-4-onyl,

wherein each of said heteroaryl groups is optionally substituted with H ₃ C-or H ₃ C-O-monosubstitution, and

wherein each H-N group in the heteroaryl group is optionally substituted with H ₃ C-N or (H) ₃ C) ₂ C(OH)-H ₂ C-N substitution;

R ¹ is H ₃ C-；

m is 2;

R ² is H or F;

n is 1; and

R ³ is H.

Another embodiment relates to compounds of formula I, wherein

R is selected from

H、F、Cl、H ₃ C-、H ₃ C-H ₂ C-、(H ₃ C) ₂ CH-、

Wherein the asterisks (—) indicate junctions/connection points;

R ¹ is H ₃ C-；

m is 2;

R ² is F;

n is 1; and

R ³ is H.

Another embodiment relates to compounds of formula I, wherein

R is

Wherein the asterisks (—) indicate junctions/connection points;

R ¹ is H ₃ C-；

m is 2;

R ² is H or F;

n is 1; and

R ³ is H.

Particularly preferred compounds are described in the experimental section below, including tautomers and stereoisomers thereof, salts thereof, or any solvates or hydrates thereof.

Known and documented by those skilled in the art may be usedThe synthesis described in the literature, obtaining the compounds according to the invention and their intermediates, is carried out, for example, using the method in the literature, "Comprehensive Organic Transformations",2 ^nd Edition,Richard C.Larock,John Wiley&Sons, 2010 and "March's Advanced Organic Chemistry",7 ^th Edition,Michael B. Smith,John Wiley&Sons,2013. Said compounds are preferably obtained by methods analogous to the more fully explained preparation methods below, in particular as described in the experimental part. In some cases, the order in which the reaction schemes are carried out may vary. Variations of these reactions known to those skilled in the art but not described in detail herein may also be used. The general method of preparing the compounds according to the invention will become apparent to the skilled person studying the following schemes. The starting compounds are commercially available or can be prepared by methods described in the literature or herein, or can be prepared in an analogous or analogous manner. Conventional protecting groups may be used to protect any corresponding functional groups in the compound prior to carrying out the reaction. These Protecting Groups can be cleaved again at a suitable stage within the reaction sequence, for example at the "Protecting Groups",3, using methods familiar to the person skilled in the art and described in the literature ^rd Edition, philip J. Kocienski, thieme,2005 and "Protective Groups in Organic Synthesis",4 ^th Edition, Peter G.M.Wuts,Theodora W.Greene,John Wiley&Sons, 2006.

The compounds I of the present invention are preferably obtained from a precursor II having a carboxylic acid functional group in protected or masked form, as shown in scheme 1; r, R ¹ 、R ² 、R ³ M and n have the meanings defined above and below. Suitable precursor groups for carboxylic acids may be, for example, carboxylic acid esters carboxylic acid amides, cyano, olefins,

Oxazole or thiazole. All these groups have been converted into carboxylic acid functions by different methods described in the organic chemistry literature and these methods are known to the person skilled in the art. Preferred precursor groups are C _1-4 -an alkyl group or a benzyl carboxylate,each of which may be additionally mono-or polysubstituted by fluorine, methyl and/or methyloxy. These ester groups can be hydrolyzed by an acid (e.g., hydrochloric acid or sulfuric acid) or an alkali metal hydroxide (e.g., lithium hydroxide, sodium hydroxide, or potassium hydroxide) to provide carboxylic acid functionality. The hydrolysis is preferably carried out in an aqueous solvent, such as water and tetrahydrofuran, 1,4-bis

An alkane, an alcohol (e.g., methanol, ethanol, and isopropanol), or dimethyl sulfoxide, at 0 to 120 ℃. Preferably under acidic conditions, e.g. in trifluoroacetic acid or hydrochloric acid, in a solvent such as dichloromethane, 1,4-bis

Tert-butyl esters are cleaved in alkanes, isopropanol or ethyl acetate. The benzyl ester is advantageously cleaved with hydrogen in the presence of a transition metal, preferably palladium on carbon. The benzyl esters carrying an electron donating group such as a methyloxy group on the aromatic ring can also be removed under oxidizing conditions; cerium Ammonium Nitrate (CAN) or 2,3-dichloro-5,6-dicyanoquinone (DDQ) are two common reagents for this process. The carboxylic acid group may also be introduced at an early stage of the synthesis, e.g. before coupling of the pyrazine moiety to the indanylamino residue, or before C-C coupling of two phenyl groups, as described in the experimental part.

Scheme 1: liberation of carboxylic acid functions to obtain the compounds of the invention

CP = COOH or a masked or protected form of COOH, e.g. CO ₂ C _1-4 Alkyl, CO ₂ CH ₂ Aryl, CON (C) _1-4 -alkyl groups) ₂ 、CN、CH＝CH ₂ Thiazol-2-yl, thiazolyl,

Azol-2-yl

The compound II can be in turn derived from indanyl amines III and pyridinesPreparation of oxazines IV (scheme 2), which pyrazines bear the carboxylic acid group or a precursor group thereof and a leaving group; r, R in scheme 2 ¹ 、R ² 、R ³ M and n have the meanings as defined above and below. The Leaving Group (LG) described in IV is replaced by the NH group in III by a nucleophilic substitution reaction on the pyrazine ring; suitable LG can be F, cl, br and I. The reaction is usually carried out in the presence of a base such as diethylamine, ethyldiisopropylamine, 1,8-diazabicyclo [5.4.0]]Undecene, carbonates (e.g. Li) ₂ CO ₃ 、Na ₂ CO ₃ 、K ₂ CO ₃ And Cs ₂ CO ₃ ) Hydroxides (e.g., liOH, naOH and KOH), alkoxides (e.g., naOMe, naOEt and KOtBu), and oxides (e.g., caO and Ag) ₂ O). Additives, e.g. silver salts (e.g. AgNO) ₃ 、AgOSO ₂ CF ₃ And Ag ₂ CO ₃ ) It may be advantageous or necessary for the reaction to proceed. Preferred solvents are dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, 1,4-bis

An alkane, tetrahydrofuran, toluene, an alcohol (e.g., ethanol or isopropanol), water, or mixtures thereof.

Alternatively, the coupling of the indanylamine III and the pyrazine IV is mediated by a transition metal catalyst. Pyrazines IV suitable for this process carry Cl, br or I as LG, and the catalyst is preferably derived from Cu, ni or Pd. The catalyst or its precursor may be a complex of a transition metal, the ligand of the complex being, for example, phosphines, such as tri-tert-butylphosphine, tricyclohexylphosphine, optionally substituted biphenyl-dicyclohexyl-phosphine, optionally substituted biphenyl-di-tert-butylphosphine, xantphos, 1,1' -bis (diphenylphosphino) ferrocene, triphenylphosphine, tritolylphosphine or trifurylphosphine, phosphite, 1,3-disubstituted imidazolebarbine, 1,3-disubstituted imidazolidinebarbine, oxamide, dibenzylideneacetone, allyl or nitrile, transition metals in elemental form, such as palladium on carbon or palladium nanoparticles, or salts of transition metals, such as fluorinated palladium on carbon or palladium nanoparticlesChloride, bromide, acetate, triflate, acetylacetonate or trifluoroacetate) which can be combined with a separately added ligand. The reaction is preferably carried out in the presence of a base, such as an alkoxide (e.g., liOtBu, naOtBu, KOtBu, naOtPert, and KOtPert), hydroxide (e.g., liOH, naOH, and KOH), hexamethyldisilazane lithium, K ₃ PO ₄ Carbonates (e.g. Cs) ₂ CO ₃ ) Or phenolates (e.g., 2,6-di-tert-butyl-4-methyl-phenol sodium salt). Additives, e.g. silver salts (e.g. AgNO) ₃ 、AgOSO ₂ CF ₃ And Ag ₂ CO ₃ ) It may be advantageous or necessary for the reaction to proceed. The coupling reaction is preferably carried out at a temperature in the range from 20 to 180 ℃ in benzene, toluene, tetrahydrofuran, 1,2-dimethyloxyethane, 1,4-bis

Alkane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, alcohol (e.g., tBuOH or tPentOH), water, or a mixture thereof. For the use of the chloro-pyrazine IV as carboxylic acid (LG = Cl and CP = COOH), particularly suitable reaction conditions include reacting chloro [2- (dicyclohexylphosphino) -3,6-dimethyloxy-2 ',4',6 '-triisopropyl-1,1' -biphenyl][2- (2-aminoethyl) phenyl group]Palladium (II) as a catalyst precursor and sodium tert-butoxide or sodium tert-amylate as a base at 60 to 110 ℃ in 1,4-bis

Alkane, toluene, tert-butanol or tert-amyl alcohol; an additional equivalent of 2- (dicyclohexylphosphino) -3,6-dimethyloxy-2 ',4',6 '-triisopropyl-1,1' -biphenyl is optionally added. The bromine-pyrazine IV (LG = Br) and the indanylamine III are also advantageously at 60 ℃ at 110 ℃ in a base (such as K) ₃ PO ₄ In dimethyl sulfoxide) with CuI and oxamide (e.g., 2- (2,6-dimethylphenylamino) -2-oxoacetic acid).

Scheme 2: preparation of precursor II

LG = leaving group, e.g. F, cl, br, I

CP = COOH or a masked or protected form of COOH, e.g. CO ₂ C _1-4 Alkyl, CO ₂ CH ₂ Aryl radicals a,

CON(C _1-4 -alkyl groups) ₂ 、CN、CH＝CH ₂ Thiazol-2-yl, thiazolyl,

Azol-2-yl

The intermediate III is conveniently obtained from an indanol V which in turn can be prepared from an indanone VI or VI' (scheme 3); r, R in scheme 3 ¹ 、R ² M and n have the meanings defined above and below.

The reduction of the keto group in compound VI or VI' is a standard transformation in organic synthesis, which can be accomplished with lithium borohydride, sodium borohydride, lithium aluminum hydride, or diisobutylaluminum hydride. Although sodium borohydride is generally used in aqueous or alcoholic solutions at 0 to 60 ℃, the other reducing agents mentioned are preferably used in inert solvents such as tetrahydrofuran, diethyl ether, dichloromethane and toluene at-80 to 60 ℃. The reduction of the keto group can also be carried out in a stereoselective manner to give the alcohol in enantiomerically enriched or enantiomerically pure form. Suitable chiral reducing agents are borane and enantiomerically pure [1,3,2] in the presence of an enantiomerically pure transition metal catalyst]

Azole boranes (Corey-Bakshi-Shibata reduction or Corey-Itsuno reduction) or combinations of formic acid, formates, hydrogen or silanes. Typical reaction conditions for the former process include borane (e.g., borane dimethylsulfide complex and (R) -or (S) -3,3-diphenyl-1-methyltetrahydro-1H, 3H-pyrrolo [1,2-c)][1,3,2]

Oxazaborolidine) in, for example, dichloromethane, toluene, methanol, tetrahydrofuran or mixtures thereof and at-10 to 60 ℃. Using chiral transition metal catalysts (e.g., ruthenium complexes such as { [ (1S, 2S) - (-) -2-amino-1,2-diphenylethyl)](4-tosyl) -amido } - (mesitylene) ruthenium (II) chloride) a hydride source (e.g., formic acid) can be used to give a high enantiomeric excess of the hydroxy compound in the presence of a base (e.g., diethylamine) in dichloromethane at-20 to 60 ℃.

The OH groups in compound V may be replaced by NH via a protective (e.g. phthalimide) or a masked (e.g. azide) amino derivative according to a two-step procedure ₂ And (4) replacing. The phthalimide may be introduced using the reaction conditions of Mitsunobu. Usually with phthalimides, phosphines and azodicarboxylates or amines in tetrahydrofuran, 1,4-bis

The conversion is carried out in an alkane, ether, toluene, benzene, dichloromethane or mixtures thereof at-30 to 100 ℃. Common phosphines are triphenylphosphine and tributylphosphine, which are often combined with dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, bis- (4-chlorobenzyl) azodicarboxylate, dibenzyl azodicarboxylate, di-tert-butyl azodicarboxylate, azodicarboxylic acid bis- (dimethylamine), azodicarboxylic acid dipiperidine or azodicarboxylic acid dimorpholine. The amino groups can be liberated from phthalimide using hydrazine in ethanol, ethylene-1,2-diamine in n-butanol, or 1-butylamine in n-butanol.

The azide groups can be introduced from the hydroxyl precursors V and V' using an azido acid or phosphoryl azide and Mitsunobu reaction conditions as described above or variants thereof. Phosphoryl azide is combined with a base (such as 1,8-diazabicyclo [5.4.0] undecene) and the conversion can also be accomplished in tetrahydrofuran or toluene at-10 to 80 ℃. The azide is converted to an amino functional group using, for example, hydrogen in the presence of a transition metal (e.g., palladium on carbon). Both processes lead to the aminoindan III in enantiomerically pure form, starting from the isomerically pure precursor V or V'.

As shown in scheme 3 and the experimental section, the phenyl residues on the indane III may be linked at various stages of the synthesis sequence by transition metal catalyzed coupling reactions. The transition metal catalyst is preferably derived from palladium, nickel, copper or iron, more preferably palladium. The active catalyst may be a complex of a transition metal with a ligand, such as a phosphine, for example tri-tert-butylphosphine, tricyclohexylphosphine, optionally substituted biphenyl-dicyclohexyl-phosphine, optionally substituted biphenyl-di-tert-butylphosphine, 1,1' -bis (diphenylphosphino) -ferrocene, triphenylphosphine, tritolylphosphine or trifurylphosphine, phosphite, 1,3-disubstituted imidazole carbene, 1,3-disubstituted imidazolidine carbene, dibenzylideneacetone, allyl or nitrile, a nanoparticle of a transition metal in elemental form, for example palladium on carbon or iron or palladium, or a salt (e.g. fluoride, chloride, bromide, acetate, triflate or trifluoroacetate). The phenyl group is preferably used as a boronic acid or ester, as a trifluoroborate or as a zinc halide, as a nucleophilic reaction partner (VI "), and as a indane derivative as a chloride, bromide or iodide, as an electrophilic reaction partner (III ', V' or VI"). Depending on the nucleophile, the reaction is preferably carried out at from 0 to 160 ℃ in benzene, toluene, ether, tetrahydrofuran, 1,2-dimethyloxyethane, 1,4-bis

Alkane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, alcohol, water or a mixture thereof. Reactions using boric acid or esters or trifluoroborates, usually in the presence of bases such as alkoxides, hydroxides (e.g. LiOH, naOH and KOH), K ₃ PO ₄ Carbonates (e.g. Li) ₂ CO ₃ ，Na ₂ CO ₃ ，K ₂ CO ₃ And Cs ₂ CO ₃ ) Amine or fluoride (e.g., KF). Additives such as halide salts, for example lithium chloride, silver salts (for example silver oxide and triflate) and/or copper salts (for example copper chloride and copper thiophene-2-carboxylate),it may be beneficial or even necessary for the reaction to proceed. The reactivity of the reaction partners (reacted carbons) can be reversed, i.e., the phenyl derivative is electrophilic and the indanyl derivative is a nucleophilic reaction partner, under the same or similar conditions, to give the same product.

Scheme 3: preparation of intermediate III

Hal＝Cl，Br，l；B(OR ^L ) ₂ ＝B(OH) ₂ ，B(OCMe ₂ CMe ₂ O)

NPG＝NH ₂ Or NH ₂ Masked or protected forms such as N3, phthalimide or NHCOOtBu

Compounds of general structure IV, wherein R is as summarized in scheme 4, can be synthesized ³ Have the meaning as defined above and below, and CP is a suitable carboxylate group.

The acrylate VII reacts with the equivalent of the methylene synthesis to give the ester IV'. Suitable reagents for this conversion include diazomethane (in the presence of a transition metal catalyst such as palladium diacetate, see, e.g., WO 2011/94890), trimethyloxosulfonium halide (in the presence of a base such as sodium hydride, see WO 2005/103032), and diiodomethane (in the presence of copper and zinc, see, e.g., US 628476). Typically, trans-acrylates are used in these reactions, yielding predominantly trans-substituted cyclopropyl esters. The literature reports enantioselective variants of this reaction, for example using diazomethane and chiral copper complexes (see, for example, tetrahedron Asymmetry 2003,14,867-872).

The pyrazines IV' are also obtained from vinyl pyrazine VIII and diazoacetic acid esters IX in the presence of a transition metal catalyst. Catalyst systems suitable for such conversion include, for example, palladium diacetate salts (see, e.g., WO 2007/104717), cobalt (II) porphyrins (see, e.g., WO 2006/103503), rhodium complexes (see, e.g., WO 2006/87169), and copper complexes (see, e.g., WO 2010/51819). The mixture of cis-and trans-cyclopropyl esters is usually predominantly in the trans system, the ratio depending on the catalyst system and the substrate used. Enantioselective reactions of this type have been reported using chiral transition metal catalysts derived from copper and cobalt (see, e.g., J.Am.chem Soc.1991,113, 726-728) and variants thereof.

Another procedure to obtain compound IV' uses epoxide X and phosphonic acid ethyl ester XI. The reaction is usually carried out in a base such as alkoxide (e.g., naOEt, naOtBu, naOtPEN, KOtBu and KOtPEN), liN (iPr) ₂ 、LiN(SiMe ₃ ) ₂ In the presence of NaH or nBuLi in a solvent (e.g., hexane, benzene, toluene, tetrahydrofuran, 1,2-dimethyloxyethane, 1,4-bisoxirane)

Alkane, dimethyl sulfoxide or mixtures thereof) at 0 to 160 ℃. The epoxides X are obtained using standard methods in organic synthesis, such as epoxidation of the corresponding olefins VIII, base-induced cyclization of the corresponding chloro-or bromohydrin derivatives, or the Corey-Chaykovsky reaction of, for example, the corresponding pyrazinecarboxaldehyde with the appropriate sulfur ylide.

Scheme 4: preparation of intermediate IV

LG = leaving group, e.g. F, cl, br, I

R′＝C _1-4 -alkyl, CH ₂ Aryl radicals

R″＝C _1-4 -alkyl radical

The proposed synthetic route may rely on the use of protecting groups. For example, potentially reactive groups present, such as hydroxyl, carbonyl, carboxyl, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups which are cleaved again after the reaction. Suitable protecting groups for the corresponding functional groups and their removal are well known to the person skilled in the art and are described in the organic synthesis literatureExamples are those described in "Protecting Groups",3 ^rd Edition, philip J.Kocienski, thieme,2005 and "Protective Groups in Organic Synthesis",4 ^th Edition，Peter G.M.Wuts， Theodora W.Greene，John Wiley&Sons，2006。

The compounds of formula I can be resolved into their enantiomers and/or diastereomers, as described below. Thus, for example, cis/trans mixtures can be separated into their cis and trans isomers, and racemic compounds can be separated into their enantiomers.

The cis/trans mixture can be separated into its cis and trans isomers by, for example, chromatography. The compounds of the formula I in racemic form can be separated into their optical enantiomers by methods known per se, and diastereomeric mixtures of compounds of the formula I can be separated into their diastereomers by methods known per se, taking advantage of their different physicochemical properties (e.g. chromatography and/or fractional crystallization); if the compounds obtained thereafter are racemates, they can be resolved into the enantiomers as described below.

The racemate is preferably isolated by column chromatography on a chiral phase, or by crystallization from an optically active solvent, or by reaction of an optically active substance which forms salts or derivatives (e.g. esters or amides) with the racemic compound. For basic compounds, salts can be formed with enantiomerically pure acids, and for acidic compounds, salts can be formed with enantiomerically pure bases. Diastereomeric derivatives are formed by enantiomerically pure auxiliary compounds, for example acids, their activated derivatives or alcohols. Thus, mixtures of salts or derivatives of the diastereomers can be separated by exploiting their different physicochemical properties (e.g., solubility differences); the free enantiomer may be separated from the pure diastereoisomeric salt or derivative by use of a suitable reagent. Optically active acids which are generally used for this purpose, as well as optically active alcohols which can be used as auxiliary residues, are known to the person skilled in the art.

As mentioned above, the compounds of formula I may be converted into salts, in particular pharmaceutically acceptable salts for pharmaceutical use. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.

Advantageously, the compounds according to the invention can also be obtained using the methods described in the examples below, and this object can also be achieved in combination with methods known to the person skilled in the art from the literature.

Terms and definitions

Terms not specifically defined herein should be given their meanings to those skilled in the art in light of the present disclosure and the context. However, as used in this specification, unless specified to the contrary, the following terms have the meanings indicated and follow the following conventions.

The terms "compound according to the invention", "compound of formula (I)", "compound of the invention" and the like denote the compounds of formula (I) according to the invention including their tautomers, stereoisomers and mixtures thereof and salts thereof, in particular said pharmaceutically acceptable salts thereof and solvates and hydrates of the compounds, including the tautomers, stereoisomers and salts thereof.

The terms "treatment" and "therapeutic" include prophylactic (i.e., disease-preventing) or therapeutic (i.e., curative and/or palliative) treatment. Thus, the term "treatment" includes the therapeutic treatment of a patient who has developed (particularly in an overt form) the condition. Therapeutic treatment may be symptomatic treatment to alleviate the symptoms of a particular indication, or symptomatic treatment (cause treatment) to reverse or partially reverse the condition of an indication or to halt or slow the progression of a disease. Thus, the compositions and methods of the invention are useful, for example, as therapeutic treatments over a period of time, as well as for chronic treatments. Furthermore, the term "treatment" includes prophylactic treatment, i.e. treating a patient at risk of developing a condition as described above, thereby reducing said risk.

When the present invention refers to a patient in need of treatment, it is primarily relevant to the treatment of mammals, in particular humans.

The term "therapeutically effective amount" means an amount of a compound of the invention to (i) treat or prevent the particular disease or condition, (ii) alleviate, ameliorate, or eliminate one or more symptoms of the particular disease or condition, or (iii) prevent or delay the onset of one or more symptoms of the particular disease or condition described herein.

The term "modulated" or "modulating" or "modulation" as used herein, unless otherwise indicated, means the activation of the G-protein coupled receptor GPR40 by one or more compounds of the present invention.

As used herein, unless otherwise specified, the terms "mediated" or "mediating" or "mediate" refer to (i) treatment, including prevention of the disease or condition, (ii) attenuation, amelioration, or elimination of one or more symptoms of the particular disease or condition, or (iii) prevention or delay of onset of one or more symptoms of the particular disease or condition described herein.

The term "substituted" as used herein means that any one or more hydrogens on the designated atom, group, or moiety is replaced with a substituent selected from the designated groups, provided that the atom's normal valence is not exceeded, and that the substitution results in an acceptably stable compound.

In the groups, groups or moieties defined below, the number of carbon atoms is generally defined before the group, e.g. C _1-6 -alkyl represents an alkyl group or a group having 1 to 6 carbon atoms. Typically, for a group comprising two or more child groups, the last named child group is the point of attachment of the group, e.g., the substituent "aryl-C _1-3 -alkyl- "denotes with C _1-3 -an alkyl-group bound aryl group bound to the core or group to which the substituent is attached.

If the compounds of the invention are described in the form of chemical names and formulae and if there are any differences, then the formula controls.

Asterisks may be used in the subformulae to indicate the bond to the defined core molecule.

The numbering of the atoms of the substituents begins with the atom closest to the core or to the group to which the substituent is attached.

For example, the term "3-carboxypropyl-group" denotes the following substituents:

wherein the carboxyl group is attached to the third carbon atom of the propyl group. The term "1-methylpropyl-", "2,2-dimethylpropyl-" or "cyclopropylmethyl-" group denotes the following groups:

In the definition of groups, the term "wherein each of the X, Y and Z groups is optionally substituted" or the like means that each group X, each group Y and each group Z are each as a separate group, or each as part of a combined group that may be substituted as defined. For example, the definition "R ^ex Denotes H, C _1-3 Alkyl radical, C _3-6 -cycloalkyl, C _3-6 -cycloalkyl-C _1-3 -alkyl or C _1-3 -alkyl-O-, wherein each alkyl is optionally substituted by one or more L ^ex By substituted, etc., in each of the foregoing groups containing the term alkyl, i.e., in each C _1-3 Alkyl radical, C _3-6 -cycloalkyl-C _1-3 -alkyl and C _1-3 In the radical-alkyl-O-, the alkyl moiety may be limited to L ^ex And (4) substitution.

Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall include tautomers and all stereoisomers, optical and geometric isomers (e.g., enantiomers, diastereomers, E/Z isomers, etc.) and racemates thereof, as well as mixtures of isolated enantiomers in varying proportions thereof, mixtures of diastereomers, or mixtures of any of the foregoing forms in which these isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof, such as hydrates, including solvates of the free compounds or solvates of salts of the compounds.

The term "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the compounds of the present disclosure, wherein the parent compound is modified by making acid or base salts thereof.

Salts of other acids than the acids mentioned above, for example salts which can be used for purifying or isolating the compounds of the invention (for example trifluoroacetate salts), also form part of the invention.

The term halogen generally denotes fluorine, chlorine, bromine and iodine.

The term "C _1-n -alkyl ", wherein n is an integer from 1 to n, alone or in combination with another group, represents an acyclic, saturated, branched or linear hydrocarbon group having from 1 to n C atoms. For example, the term "C _1-5 Alkyl "includes the group H ₃ C-、H ₃ C-CH ₂ -、H ₃ C-CH ₂ -CH ₂ -、 H ₃ C-CH(CH ₃ )-、H ₃ C-CH ₂ -CH ₂ -CH ₂ -、H ₃ C-CH ₂ -CH(CH ₃ )-、H ₃ C-CH(CH ₃ )-CH ₂ -、H ₃ C-C(CH ₃ ) ₂ -、H ₃ C-CH ₂ -CH ₂ -CH ₂ -CH ₂ -、H ₃ C-CH ₂ -CH ₂ -CH(CH ₃ )-、 H ₃ C-CH ₂ -CH(CH ₃ )-CH ₂ -、H ₃ C-CH(CH ₃ )-CH ₂ -CH ₂ -、H ₃ C-CH ₂ -C(CH ₃ ) ₂ -、 H ₃ C-C(CH ₃ ) ₂ -CH ₂ -、H ₃ C-CH(CH ₃ )-CH(CH ₃ ) -and H ₃ C-CH ₂ -CH(CH ₂ CH ₃ )-。

The term "C _1-n -alkylene ", wherein n is an integer from 1 to n, alone or in combination with another group, represents an acyclic, linear or branched divalent alkyl group having from 1 to n carbon atoms. For example the term C _1-4 Alkylene radicals including- (CH) ₂ )-、-(CH ₂ -CH ₂ )-、-(CH(CH ₃ ))-、-(CH ₂ -CH ₂ -CH ₂ )-、 -(C(CH ₃ ) ₂ )-、-(CH(CH ₂ CH ₃ ))-、-(CH(CH ₃ )-CH ₂ )-、-(CH ₂ -CH(CH ₃ ))-、 -(CH ₂ -CH ₂ -CH ₂ -CH ₂ )-、-(CH ₂ -CH ₂ -CH(CH ₃ ))-、-(CH(CH ₃ )-CH ₂ -CH ₂ )-、 -(CH ₂ -CH(CH ₃ )-CH ₂ )-、-(CH ₂ -C(CH ₃ ) ₂ )-、-(C(CH ₃ ) ₂ -CH ₂ )-、 -(CH(CH ₃ )-CH(CH ₃ ))-、-(CH ₂ -CH(CH ₂ CH ₃ ))-、 -(CH(CH ₂ CH ₃ )-CH ₂ )-、-(CH(CH ₂ CH ₂ CH ₃ ))-、-(CHCH(CH ₃ ) ₂ ) -and-C (CH) ₃ )(CH ₂ CH ₃ )-。

The term "C _2-n -alkenyl "is intended to mean having at least two carbon atoms as defined under" C _1-n -a group as defined in alkyl ", wherein at least two of these carbon atoms are connected to each other by a double bond. For example the term C _2-3 -alkenyl comprises-CH = CH ₂ 、-CH＝CH-CH ₃ 、-CH ₂ -CH＝CH ₂ 。

The term "C _2-n -alkynyl "is intended to mean a radical having at least two carbon atoms as defined under" C _1-n -alkyl ", where at least two of these carbon atoms are connected to each other by a triple bond. For example the term C _2-3 Alkynyl includes-C.ident.CH, -C.ident.C-CH ₃ 、-CH ₂ -C≡CH。

The term "C _3-n -cycloalkyl ", wherein n is an integer from 4 to n, alone or in combination with another group, represents a cyclic, saturated, unbranched hydrocarbon radical having 3 to n C atoms. Such cyclic groups may be monocyclic, bicyclic, tricyclic or spirocyclic, most preferably monocyclic. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo [3.2.1 ].]Octyl, spiro [4.5 ]]Decyl, norpinyl, norbornyl, norcareyl, adamantyl, and the like.

A plurality of the terms mentioned above can be reused in the definitions of formulae or radicals and in each case independently of one another have one of the meanings given above.

Pharmacological Activity

The activity of the compounds of the invention can be demonstrated by the following tests:

IP Using IPone assay System ₁ Accumulation measurement-1321N 1 cells stably expressing the human GPR40 receptor (Euroscreen, belgium) were inoculated 24 hours prior to the assay in a white 384-well plate containing 10% fcs, 1% sodium pyruvate, and 400 μ g/mLG 418. IP was determined according to the manufacturer's description (Cisbio Bioassays, france) ₁ . Briefly, by applying stimulation buffer (Hepes 10mM, caCl) ₂ 1mM、MgCl ₂ 0.5mM, KCl 4.2mM, naCl 146mM, glucose 5.5mM and LiCl 50mM, pH 7.4) was substituted for the medium to start the assay. By adding a compound diluted with a stimulation buffer containing LiCl, the content of CO was 5% at 37 ℃% ₂ Cells were stimulated for 1 hour. The assay was terminated by the addition of HTRF-conjugate (IP 1-d2 and anti-IP 1 cryptate Tb) and lysis buffer as supplied by the manufacturer. After 1 hour incubation at room temperature, enVision was used ^TM Perkin Elmer measurement panel. The Assay Explorer 3.3 software (Accelrys, inc.) was then used, using IP ₁ Interpolation of the reference curve and subsequent sigmoidal curve fitting (allowing variable Hill slope to be obtained), pEC was calculated using the fluorescence ratio obtained at 665/615nM ₅₀ The value is obtained.

The compounds according to the invention generally have a molar mass of from about 1nM to about 10. Mu.M, preferably less than 1. Mu.M, more preferably less than 1EC of 00nM ₅₀ The value is obtained.

EC of the Compounds according to the invention ₅₀ The values are shown in the table below. The numbering of the compounds corresponds to the numbering of the examples in the experimental section.

Table 2:

chemical stability

Degradation kinetics are used to mimic the chemical stability of the compound in the acidic part of the gastrointestinal tract. The compounds of the present invention show superior chemical stability in acidic aqueous media (pH around 1.2) compared to a number of compounds explicitly disclosed in WO 2013/178575. Therefore, their use as medical drugs for the treatment of human diseases is less limited and less cumbersome.

The chemical stability of the compounds of the invention at a pH of about 1.2 was determined as follows:

the compound was dissolved in an HPLC vial containing a mixture of acetonitrile/0.1M aqueous HCl (2. The vials were then transferred to an HPLC autosampler system and maintained at a temperature of 37 ℃. The first sample was taken and immediately injected into a standard HPLC system with a UV DAD detector. Further samples were injected after 2, 4, 6, 8 and 10 hours. Determination of the recovery [% of Compound injected in each case by Using HPLC Standard gradient method]Thereby determining the amount of degraded compound. Therefore, the peak Area (AU) of the main peak injected for the first time was measured _t0 ) And set it to 100%. The peak Area (AU) of the further injected main peak was also determined _{tn,n＝2、4、6、8、10} ) And is expressed As (AU) _t0 )/(AU _{tn,n＝2、4、6、8、10} )[％]The fraction of (c).

At a pH of about 1.2, the amount of degradation of the compounds according to the invention after 2 hours, as determined as described above, is typically significantly below 1.5%, mostly below 0.5%.

The following table compares the amount of degradation after 2 hours of the compounds according to the invention and the compounds in WO2013/178575 at a pH of about 1.2 (see table 3 below for their structure).

Table 3:

the chemical structure of the examples in case WO2013/178575 is as follows.

Solubility in water

The aqueous solubility of the compounds of the invention was determined by comparing the amount dissolved in the buffer with the amount in acetonitrile/water (1/1) solution. Starting from a 10mM DMSO stock solution, aliquots were diluted with acetonitrile/water (1/1) or buffer, respectively. After 24 hours of shaking, the solution was filtered and analyzed by LC-UV. The amount dissolved in the buffer was compared with the amount in the acetonitrile solution.

At DMSO concentrations of 2.5%, the solubility is typically 0.001 to 0.125mg/mL. If more than 90% of the compound is dissolved in the buffer, the value is marked with ">".

The compounds of the invention show higher solubility at moderate pH (pH 6.8) compared to the direct structural counterparts explicitly disclosed in WO 2013/178575. Therefore, their development and application are more convenient and reliable. Data for selected compounds of the invention and their direct structural counterparts in WO2013/178575 are compiled after the chapter "inhibition of CYP-2C 9".

Inhibition of CYP-2C8

The inhibition of the dethylation of amodiaquine (which is catalyzed by cytochrome P450 2C 8-isozyme) by the tested compounds was determined with human liver microsomes at 37 ℃. All assays were performed in 96 well platesOn a robotic system of (1). The final incubation volume contained TRIS buffer (0.1M), mgCl ₂ (5 mM), human liver microsomes (0.05 mg/mL), amodiaquine (1. Mu.M), and five different concentrations of test compound or no compound (high concentration control, in duplicate, e.g., the highest concentration of 10-50. Mu.M and its subsequent serial 1:4 dilutions). After a short pre-incubation period, the reaction was started with cofactor (NADPH, 1 mM) and stopped by cooling the incubation to 8 ℃ and then by adding a volume of acetonitrile. An internal standard solution (stable isotope d 5-desethylamodiaquine) was added after quenching incubation. The peak areas of the analyte (= formed metabolite) and internal standard were determined by LC-MS/MS. The resulting peak area ratios of analyte to internal standard in these incubations were compared to the activity of the control group without test compound. In each assay run, the IC of the positive control inhibitor (Montelukast) was determined ₅₀ . The IC of the experiment was calculated by least squares regression according to the following equation ₅₀ The value:

% control activity = (100% control activity/(1 + (I/IC) ₅₀ )S))-B

Wherein I = inhibitor concentration; s = slope coefficient; b = background activity (lower plateau of inhibition curve)

If at the lowest concentration of test compound, the inhibition of the reaction has already taken place>50% then IC ₅₀ Is determined as "<Lowest concentration tested "(generally ″)<0.4. Mu.M). If at the highest concentration of test compound, the inhibition of this reaction is still present<50% then IC ₅₀ Is determined as ">Highest concentration tested "(usually>50μM)。

The compounds of the invention show less inhibition of cytochrome P450 2C 8-isozymes than the direct structural counterparts of the compounds of the invention specifically disclosed in WO 2013/178575. Thus, the likelihood of them causing unwanted side effects is reduced. Data for selected compounds of the invention and their direct structural counterparts in WO2013/178575 are presented after the compiled section "inhibition of CYP-2C 9".

Inhibition of CYP-2C9

Human liver microsomal assay of test Compound pairs at 37 deg.CInhibition of hydroxylation of diclofenac (this hydroxylation being catalyzed by cytochrome P450 2C 9-isozyme). All assays were performed on a robotic system in 96-well plates. The final incubation volume contained TRIS buffer (0.1M), mgCl ₂ (5 mM), human liver microsomes (0.1 mg/mL), diclofenac (10. Mu.M) and five different concentrations of the test compound or no compound (high concentration control, in duplicate, e.g., the highest concentration of 10-50. Mu.M and its subsequent serial 1:4 dilutions). After a short pre-incubation period, the reaction was started with cofactor (NADPH, 1 mM) and stopped by cooling the incubation to 8 ℃ and then by adding a volume of acetonitrile. After incubation quenching, an internal standard solution (stable isotope) is added ¹³ C6-hydroxy diclofenac). The peak areas of the analyte (= metabolite formed) and the internal standard were determined by LC-MS/MS. The peak area ratios of the analyte to internal standard obtained in these incubations were compared to the control activity without test compound. In each assay run, the IC of the positive control inhibitor (sulfaphenazole) was determined ₅₀ . The IC of the experiment was calculated by least squares regression according to the following equation ₅₀ The value:

% control activity = (100% control activity/(1 + (I/IC) ₅₀ )S))-B

If at the lowest concentration of test compound, the inhibition of the reaction has already taken place>50% then IC ₅₀ Is determined as "<Lowest concentration tested "(generally)<0.4. Mu.M). If at the highest concentration of test compound, the inhibition of this reaction is still present<50% then IC ₅₀ Is determined as ">Highest concentration tested "(usually>50μM)。

The compounds of the invention show a weaker inhibition of cytochrome P450 2C 9-isozymes compared to the structural counterparts of the compounds of the invention explicitly disclosed in WO 2013/178575. Thus, the likelihood of them causing unnecessary side effects is reduced. The following compilation gives data for selected compounds of the invention and their direct structural counterparts in WO 2013/178575.

The following compilation demonstrates the superiority of selected compounds of the invention over the compounds of WO2013/178575 in terms of chemical stability, solubility, CYP-2C8 inhibition and CYP-2C9 inhibition by a head-to-head comparison (head-to-head comparison) of their direct structural analogs.

HCN4 inhibition

Furthermore, the compounds of the present invention show superiority over certain potent GPR40 agonists in terms of unwanted inhibitory activity on the ion channel HCN4 (potassium/sodium hyperpolarized activated cyclic nucleotide gated channel 4).

HCN4 determination procedure

Preparation of the compound:

compounds in solid form were prepared in DMSO at 300x final assay concentration (10, 3,1 and 0.3 μ M). All 300x DMSO stock solutions were transferred to master plates and transferred to assay plates, where 2 μ Ι of each 300x solution was placed per well. All assay plates were stored at-80 ℃ until the day of assay.

On the day of assay, the appropriate assay plate was thawed at room temperature, centrifuged, 198 μ L of external solution was added and mixed well. Dilutions of 1. Further 1:3 dilutions were made after addition of cells in the IonWorks platform, resulting in an overall dilution of 1.

On each assay plate, at least 8 wells were reserved for vehicle controls (0.3% dmso), and each positive control had at least 8 wells. At maximum blocking and approximate IC ₅₀ Positive controls were tested at concentration. The positive control compounds are summarized below。

Ion channel positive controls and concentrations:

50 μ M and 3mM cesium chloride.

Electrophysiology recording solution:

external solution:

pH 7.3 (titration with 10M NaOH)

Internal standard solution:

pH 7.3 (titration with 10M KOH)

Electrical access to the cell interior was obtained using amphotericin B at a final concentration of 200. Mu.g/ml in the internal recording solution.

Experimental protocol and data analysis:

the single pulse that causes HCN4 current in humans comes from the following holding potential

-potential from 30mV to-110 mV for 4 seconds and then back to

-30 mV. The voltage protocol (Pre) was applied, compounds were added, incubated for 600 seconds, and the voltage protocol (Post) was applied last time on IonWorks Quattro.

The maximum inward current induced when stepping from the holding potential-30 mV to-110 mV is the measured parameter. All data were filtered to obtain seal quality (seal quality), seal drop (seal drop) and current amplitude (current amplitude). The maximum current amplitude of the single hyperpolarisation pulse before (Pre) and after (Post) the compound addition is calculated and the amount of blocking (block) is calculated by dividing the current amplitude after the compound addition by the current amplitude before the compound addition.

Selection criteria for active recording:

in view of their ability to modulate the activity of the G-protein coupled receptor GPR40, in particular the agonist activity, the compounds of general formula I according to the present invention, including the corresponding salts thereof, are ideally suited for the treatment of all these diseases or conditions which may be affected or modulated by the activation of the G-protein coupled receptor GPR40.

The invention therefore relates to compounds of the general formula I as medicaments.

Furthermore, the present invention relates to the use of a compound of general formula I or a pharmaceutical composition according to the invention for the treatment and/or prevention of a disease or condition mediated by the activation of the G-protein coupled receptor GPR40 in a patient, preferably a human.

In another aspect, the invention relates to a method of treatment of a disease or condition mediated by activation of the G-protein coupled receptor GPR40 in a mammal, comprising the step of administering to a patient in need of such treatment, preferably a human, a therapeutically effective amount of a compound or pharmaceutical composition of the invention.

Diseases and conditions mediated by agonists of the G-protein coupled receptor GPR40 include metabolic diseases or conditions. According to one aspect, the compounds and pharmaceutical compositions of the invention are particularly suitable for the treatment of diabetes, especially type 2 diabetes, type 1 diabetes, diabetic complications (such as, for example, retinopathy, nephropathy or neuropathy, diabetic foot, ulcers or macroangiopathy), metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolism disorders, insulin resistance, metabolic syndrome, dyslipidemia of different origin, atherosclerosis and related diseases, obesity, hypertension, chronic heart failure, edema and hyperuricemia.

The compounds and pharmaceutical compositions of the invention are also useful for preventing beta cell degeneration, such as pancreatic beta cell apoptosis or necrosis. The compounds and pharmaceutical compositions of the invention are also useful for improving or restoring the function of pancreatic cells, and are also useful for increasing the number and size of pancreatic beta cells.

Thus according to another aspect, the present invention relates to compounds of formula I and pharmaceutical compositions according to the invention for preventing, delaying, slowing the progression of and/or treating metabolic diseases, in particular improving glycemic control and/or beta cell function in a patient.

In another aspect, the present invention relates to compounds of formula I and pharmaceutical compositions according to the present invention for use in preventing, delaying, slowing the progression of, and/or treating type 2 diabetes, overweight, obesity, diabetic complications and related pathological conditions.

Furthermore, the compounds and pharmaceutical compositions according to the invention are suitable for one or more of the following methods of treatment:

for preventing, delaying, slowing the progression of or treating metabolic diseases, such as for example type 1 diabetes, type 2 diabetes, insufficient glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, syndrome X, metabolic syndrome, obesity, hypertension, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, endothelial dysfunction or bone related diseases (such as osteoporosis, rheumatoid arthritis or osteoarthritis);

-for improving glycemic control and/or for reducing fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1c;

for preventing, delaying, slowing or reversing the progression of impaired glucose tolerance, insulin resistance and/or metabolic syndrome to type 2 diabetes;

-for preventing, delaying, slowing the progression of diabetes or treating a condition or disease selected from diabetic complications, such as for example retinopathy, nephropathy or neuropathy, diabetic foot, ulcers or macroangiopathy;

-for weight loss or to prevent weight gain or to assist weight loss;

-for preventing or treating the degradation of pancreatic beta cells and/or improving and/or restoring the function of pancreatic beta cells and/or restoring the function of pancreatic insulin secretion;

-for maintaining and/or improving insulin sensitivity and/or preventing or treating hyperinsulinemia and/or insulin resistance.

In particular, the compounds and pharmaceutical compositions according to the invention are suitable for the treatment of obesity, diabetes (including type 1 and type 2 diabetes, preferably type 2 diabetes) and/or diabetic complications (such as, for example, retinopathy, nephropathy or neuropathy, diabetic foot, ulcers or macroangiopathy).

The compounds according to the invention are most particularly suitable for the treatment of type 2 diabetes.

The daily dose of a compound of formula I is usually in the range of 0.001 to 10mg per kg body weight, for example 0.01 to 8mg per kg body weight of the patient. Each dosage unit may conveniently contain from 0.1 to 1000mg, for example from 0.5 to 500mg.

The actual therapeutically effective amount or therapeutic dose will, of course, depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease. In any event, the compound or composition will be administered in a dose and manner that allows for a therapeutically effective amount to be delivered, based on the patient's unique condition.

The compounds, compositions according to the invention, including any combination with one or more other therapeutic agents, may be administered by the oral, transdermal, inhalation, parenteral or sublingual routes. Among these possible methods of administration, oral or intravenous administration is preferred.

Pharmaceutical composition

Formulations suitable for administering a compound of formula I, optionally in combination with one or more other therapeutic agents, will be apparent to those of ordinary skill in the art and include, for example, tablets, pills, capsules, suppositories, troches, lozenges, solutions, syrups, elixirs, sachets, injections, inhalants, powders and the like. Oral formulations are particularly preferred in solid form such as, for example, tablets or capsules. The content of the pharmaceutically active compound is advantageously in the range of 0.1 to 90% by weight, for example 1 to 70% by weight, of the total composition.

For example, suitable tablets may be obtained by mixing one or more compounds according to formula I with known excipients (e.g. inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants). The tablet may also be composed of multiple layers. The particular excipients, carriers and/or diluents suitable for use in the desired formulation will be well known to those skilled in the art based upon their expertise, and preferably those suitable for the particular formulation required and the desired method of administration. The preparations (preparation or formulation) according to the invention can be prepared using methods known per se to the person skilled in the art. Such as, for example, by mixing or combining at least one compound of formula I according to the invention or a pharmaceutically acceptable salt of the compound and one or more excipients, carriers and/or diluents.

Combination therapy

The compounds of the invention may be further combined with one or more, preferably one, additional therapeutic agents. According to one embodiment, the further therapeutic agent is selected from therapeutic agents that contribute to the treatment of the diseases or conditions described above, in particular associated with metabolic diseases or conditions, such as diabetes, obesity, diabetic complications, hypertension, hyperlipidemia. Other therapeutic agents suitable for such a combination include, inter alia, drugs such as those which enhance the therapeutic effect of one or more of the active substances corresponding to one of the indications mentioned above and/or which allow a reduction in the dose of one or more of the active substances.

The compounds of the invention may therefore be combined with one or more other therapeutic agents selected from antidiabetic agents, agents for treating overweight and/or obesity and agents for treating hypertension, heart failure and/or atherosclerosis.

Antidiabetic agents are for example metformin, sulfonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR- (alpha, gamma or alpha/gamma) agonists or modulators, alpha-glucosidase inhibitors, DPPIV inhibitors, SGLT2 inhibitors, insulin and insulin analogues, GLP-1 and GLP-1 analogues or amylin and amylin analogues, cyclic sugars (cyclosets), 11 beta-HSD inhibitors. Other suitable combination formulations are inhibitors of protein tyrosine phosphatase 1, substances which influence a deregulated glucose production in the liver, for example glucose-6-phosphatase inhibitors, or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrogenase kinase, alpha 2-antagonists, CCR-2 antagonists or glucokinase activators. The lipid lowering agent or agents may also be suitable combination formulations, such as e.g. HMG-CoA-reductase inhibitors, fibrates, nicotinic acid and its derivatives, PPAR- (alpha, gamma or alpha/gamma) agonists or modulators, PPAR-delta agonists, ACAT inhibitors or cholesterol absorption inhibitors, e.g. bile acid binding substances, e.g. ileal bile acid transport inhibitors, MTP inhibitors or HDL-raising compounds such as CETP inhibitors or ABC1 modulators.

Therapeutic agents useful for the treatment of overweight and/or obesity are, for example, antagonists of the cannabinoid 1 receptor, antagonists of the MCH-1 receptor, MC4 receptor agonists, NPY5 or NPY2 antagonists, β 3-agonists, leptin or leptin analogs, 5HT2c receptor agonists.

Therapeutic agents for the treatment of hypertension, chronic heart failure and/or atherosclerosis are, for example, A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, beta-blockers, ca-antagonists, centrally acting antihypertensive agents, antagonists of alpha-2-adrenoceptors, inhibitors of neutral endopeptidase, inhibitors of platelet aggregation and other suitable substances or combinations thereof. Angiotensin II receptor antagonists are preferably used for the treatment or prevention of hypertension and diabetic complications, which are usually combined with diuretics such as hydrochlorothiazide.

The dosage of the above combination formulations is often 1/5 of the normally recommended minimum dosage to 1/1 of the normally recommended dosage.

Preferably, the compounds of the invention and/or pharmaceutical compositions comprising the compounds of the invention are administered in conjunction with exercise and/or diet, optionally in combination with one or more other therapeutic agents.

Thus, in a further aspect, the present invention relates to the use of a compound according to the present invention, in combination with one or more other therapeutic agents as described above and below, for the treatment of a disease or condition which may be affected by or mediated by the activation of the G-protein coupled receptor GPR40, in particular as described above and below.

In another aspect the invention relates to a method for the treatment of a disease or condition mediated by activation of the G-protein coupled receptor GPR40 in a patient comprising the steps of: a therapeutically effective amount of a compound of the invention in combination with a therapeutically effective amount of one or more other therapeutic agents, as described above and below, is administered to the patient, preferably a human, in need of such treatment.

The combined use of the compounds according to the invention and the other therapeutic agents can be carried out simultaneously or alternatively.

The compound according to the invention and the one or more other therapeutic agents may both be present in one dosage form, e.g. a tablet or capsule, or may be separated in two identical or different dosage forms, e.g. as a so-called kit of parts.

Thus, in another aspect, the present invention relates to a pharmaceutical composition comprising a compound according to the present invention and one or more other therapeutic agents as described above and below, and optionally one or more inert carriers and/or diluents.

Other features and advantages of the present invention will be apparent from the following more detailed description of the embodiments, which, by way of example, illustrate the principles of the invention.

Examples

The terms "ambient temperature" and "room temperature" are used interchangeably and refer to a temperature of about 20 ℃.

As a rule, of the compounds prepared ¹ H-NMR and/or mass spectra have been obtained.

Depending on the purification method and conditions used, the intermediates and examples reported below which carry basic or acidic groups can be obtained as corresponding salts or neutral compounds. The salts can be converted to their corresponding neutrals by standard methods known to those skilled in the art.

HPLC analytical parameters for characterization of the product (TFA for trifluoroacetic acid):

intermediate 1

Trans-2- (5-bromo-pyrazin-2-yl) -cyclopropanecarboxylic acid ethyl ester

Step 1: 2-bromo-5-vinyl-pyrazines

At room temperature, adding Na ₂ CO ₃ The solution (2 mol/L in water, 5.3 mL) was charged to a flask equipped with a stirrer, 2,5-dibromo-pyrazine (1.00 g), potassium vinyltrifluoroborate (0.56 g), tetrahydrofuran (6 mL) and toluene (2 mL). The mixture was purged with argon for 5 minutes, then 1,1' -bis (diphenylphosphino) ferrocene-dichloropalladium (II) (0.15 g) was added. The mixture was stirred at 80 ℃ overnight. After cooling to room temperature, water and ethyl acetate were added, and the resulting mixture was filtered. The organic phase was separated and carefully concentrated. The residue is chromatographed on silica gel (cyclohexane)Ethyl acetate 49). Mass spectrometry (ESI) ⁺ )：m/z＝185/187(Br)[M+H] ⁺ 。

Step 2: trans-2- (5-bromo-pyrazin-2-yl) -cyclopropanecarboxylic acid ethyl ester

A mixture of ethyl diazoacetate (13% in dichloromethane; 2.2 mL), 2-bromo-5-vinyl-pyrazine (0.45 g) and xylene (5 mL) was stirred at 100 ℃ for 4 hours. After cooling to room temperature, 1M aqueous HCl was added and the resulting mixture was stirred vigorously for 15 minutes. The mixture was extracted with ethyl acetate and the organic extract was concentrated. The residue was chromatographed on silica gel (cyclohexane/ethyl acetate 49 1 → 4:1) to give the title compound in racemic trans configuration. Mass spectrometry (ESI) ⁺ )： m/z＝271/273(Br)[M+H] ⁺ 。

Intermediate 2 and intermediate 3

(1S, 2S) -2- (5-bromo-pyrazin-2-yl) -cyclopropanecarboxylic acid ethyl ester (intermediate 2) and (1R, 2R) -2- (5-bromo- Pyrazin-2-yl) -cyclopropanecarboxylic acid ethyl ester (intermediate 3)

Step 1: 2-bromo-5-oxiranyl-pyrazines

N-bromosuccinimide (NBS, 2.51 g) was added to a flask equipped with a stir bar, 2-bromo-5-vinyl-pyrazine (2.50 g), t-butanol (18 mL), and water (38 mL) at room temperature. The mixture was stirred at 55 ℃ for 1.5 hours. After cooling to room temperature, the mixture was cooled in an ice bath and NaOH solution (4 mol/L in water, 10 mL) was added dropwise. The mixture was stirred in the ice bath for 15 minutes, then water, na were added ₂ S ₂ O ₃ Aqueous solution and diethyl ether. The organic phase is separated, washed with water and dried (Na) ₂ SO ₄ ). The solvent was carefully removed and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 49. Mass spectrometry (ESI) ⁺ )：m/z＝201/203(Br)[M+H] ⁺ 。

A solution of sodium tert-amylate (30% in 2-methyltetrahydrofuran, 6.9 mL) was added dropwise to a flask equipped with a stirrer, triethyl phosphonoacetate (3.3 mL) and toluene (50 mL) at room temperature. The mixture was stirred at about 35 ℃ for 20 minutes, then 2-bromo-5-oxiranyl-pyrazine (3.20 g) in toluene (15 mL) was added. The mixture was stirred at 105 ℃ for 1 hour. After cooling to room temperature, the mixture was quenched with 1M H ₃ PO ₄ The mixture was washed with aqueous solution and brine, and dried (MgSO ₄ ). The mixture was concentrated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 49. Mass spectrometry (ESI) ⁺ )：m/z＝271/273(Br)[M+H] ⁺ 。

Chromatographic separation of enantiomers:

SFC separation was performed on chiral phase and pure enantiomers were obtained from the racemic mixture (column:

amylose-2 (Phenomenex Inc.), 5 μm,250mm x 20mm; eluent: scCO ₂ Methanol 95, 5, 40 ℃,150bar, 60ml/min):

(1s, 2s) -2- (5-bromo-pyrazin-2-yl) -cyclopropanecarboxylic acid ethyl ester: t is t _R ＝2.26min

(1r, 2r) -2- (5-bromo-pyrazin-2-yl) -cyclopropanecarboxylic acid ethyl ester: t is t _R ＝2.00min

Intermediate 4

(1S, 2S) -2- (5-chloro-pyrazin-2-yl) -cyclopropanecarboxylic acid ethyl ester

Step 1: 5-chloro-pyrazine-2-carbonyl chloride

N, N-dimethylformamide (1 drop) was added to a flask charged with a stirrer, 5-chloro-pyrazine-2-carboxylic acid (13.17 g), thionyl chloride (25 mL) and toluene (200 mL) at room temperature. The mixture was stirred at 60 ℃ overnight. After cooling to room temperature, the mixture was concentrated and the residue was freed of volatile residues by repeated evaporation three times with toluene.

Step 2: 2-chloro-1- (5-chloro-pyrazin-2-yl) -ethanone

Trimethylsilyl diazomethane (2 mol/L in hexane, 50 mL) was added dropwise over 3.5 hours to a stirred, cooled solution of 5-chloro-pyrazine-2-carbonyl chloride (11.80 g) in tetrahydrofuran in an ice bath. After complete disappearance of the starting material (TLC or HPLC), the mixture is cooled to about-15 ℃ and 1,4-bis are added over one minute

HCl in alkane (4 mol/L,50 mL). The mixture was stirred for 10 minutes, then water was added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (80 mL). With water and NaHCO ₃ The combined organic phases were washed with aqueous solution until neutral and dried (MgSO) ₄ ). The mixture was filtered and the drying agent was washed with ethyl acetate (80 mL) to give a combined solution of the title compound, which was used as such in the next reaction step.

Step 3: (R) -1- (5-chloro-pyrazin-2-yl) -2-chloro-ethanol

(1S,2S)-Cp*RhCl(TsNCHPhCHPhNH ₂ ) (0.33 g; prepared from (1s, 2s) - (+) -N- (4-tosyl) -1,2-diphenylethylenediamine and pentamethyl-cyclopentadienyl-rhodium chloride dimer as described in Organometallics 2009,28,1435-1446 or chem.commun.2015,52, 362-365; alternatively, the catalyst was prepared in situ by mixing the two components in a reaction flask) was added to the solution of 2-chloro-1- (5-chloro-pyrazin-2-yl) -ethanone prepared in step 2 and the resulting mixture was cooled to-30 ℃. To the mixture was added dropwise a mixture of diethylamine and formic acid (prepared by adding diethylamine (45 mL) to formic acid (12 mL) at room temperature), and the mixture was stirred for 5 minutes. The mixture was stirred while warming to room temperature overnight. 1M NaHCO was added ₃ Aqueous solution, and the mixture was stirred vigorously. Mixing the mixture with diatomaceous earth(Celite) filtration and separation of the organic phase of the filtrate. The aqueous phase was extracted with ethyl acetate and the organic phases were combined. The organic phase was washed with water and brine and dried (MgSO ₄ ). The solvent was evaporated to give the title compound, which was used as such in the next reaction step.

Step 4: (R) -2-chloro-5-oxiranyl-pyrazines

Aqueous NaOH (4 mol/L,20 mL) was added to a flask equipped with a stirrer, (R) -1- (5-chloro-pyrazin-2-yl) -2-chloro-ethanol (12.9 g), and tetrahydrofuran (80 mL) at room temperature. The mixture was stirred overnight. The mixture was diluted with ethyl acetate and diluted with 1M H ₃ PO ₄ The mixture was washed with aqueous solution and brine, dried (MgSO ₄ ) And concentrated. The residue is chromatographed on silica gel (petroleum ether/ethyl acetate) to give the title compound. Mass spectrometry (ESI) ⁺ )：m/z＝157/159(Cl)[M+H] ⁺ 。

Step 5: (1S, 2S) -2- (5-chloro-pyrazin-2-yl) -cyclopropanecarboxylic acid ethyl ester

A solution of sodium tert-amylate (70 g) in tetrahydrofuran (250 mL) was added over 15 minutes to a flask equipped with a stirrer and triethyl phosphonoacetate (125 mL) cooled in an ice bath. The mixture was stirred for 15 minutes while cooling, and then stirred for 30 minutes at room temperature. Thereafter, the mixture was added dropwise to a 90 ℃ solution of (R) -2-chloro-5-oxiranyl-pyrazine (34.3 g) in toluene (125 mL) over 45 minutes. The mixture was stirred at 90 ℃ for an additional 15 minutes and then at room temperature for 1 hour. With 1M H ₃ PO ₄ The aqueous solution slightly acidifies the mixture (pH about 5-6). The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried (MgSO) ₄ ) And concentrated. The residue is chromatographed on silica gel (petroleum ether/ethyl acetate) to give the title compound. Mass spectrometry (ESI) ⁺ )： m/z＝227/229(Cl)[M+H] ⁺ 。

Intermediate 5

(1S, 2S) -2- (5-chloro-pyrazin-2-yl) -cyclopropanecarboxylic acid

A4M aqueous NaOH solution (45 mL) was added to a flask equipped with a stirrer, (1S, 2S) -ethyl 2- (5-chloro-pyrazin-2-yl) -cyclopropanecarboxylate (27.2 g) and tetrahydrofuran (160 mL) at room temperature. The mixture was stirred at room temperature overnight. Water (80 mL) was added and most of the tetrahydrofuran was evaporated. The aqueous residue was washed with diethyl ether and then adjusted to pH 4-5 with 4M aqueous HCl. The mixture was stirred for 30 minutes and the precipitate formed was isolated by filtration, washed with water and dried in a desiccator to give the first crop of the title compound. The aqueous filtrate was adjusted to pH 1 with 4M aqueous HCl and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO) ₄ ) And concentrated to give a second crop of the title compound. Mass spectrometry (ESI) ^- )：m/z＝197/199(Cl)[M-H] ^- 。

The multiple batches of intermediate 5 obtained from intermediate 4 and hydrolyzed as described above typically have an enantiomeric purity (ee) of 40% to 80%.

The enantiomeric purity of multiple batches of intermediate 5 can be upgraded to >95% ee by applying the following procedure:

(S) -1-phenylethylamine (11.6 mL) was added to a solution of (1S, 2S) -2- (5-chloro-pyrazin-2-yl) -cyclopropanecarboxylic acid (18.1 g) in isopropanol (270 mL) at 80 ℃. The solution was stirred at 80 ℃ for 15 minutes and then left at room temperature overnight without stirring. The precipitate was isolated by filtration, washed with isopropanol and dried at 40 ℃ to give (S) -1-phenylethylammonium (1s, 2s) -2- (5-chloro-pyrazin-2-yl) -cyclopropanecarboxylate (if the diastereomeric purity of the ammonium salt was insufficient, the precipitate was recrystallized again from isopropanol).

The (S) -1-phenylethylammonium carboxylate (14.8 g) was suspended in ethyl acetate (60 mL) and 1M aqueous HCl (47 mL) was added. The mixture was stirred until all solids were dissolved. The organic phase was separated and washed with brine. Drying (MgSO 4) ₄ ) And the organic phase was concentrated. The residue was recrystallized from ether/pentane to give (1S, 2S) -one in the pure enantiomeric form2- (5-chloro-pyrazin-2-yl) -cyclopropane-carboxylic acid.

Intermediate 6

(R) -4- [2,6-dimethyl-4- (2-methyl-2H-tetrazol-5-yl) -phenyl]-indan-1-ylamine

Step 1: (S) -4- (4,4,5,5-tetramethyl- [1,3,2]Dioxaborolan-2-yl) -indan-1-ol

Potassium acetate (2.0 g) was added to (S) -4-bromo-indan-1-ol (2.5 g; see, for its preparation, WO 2013/144098), bis (pinacolato) diboron (3.3 g) and 1,4-dibenz with stirrer at room temperature

Alkane (50 mL) in a flask. The mixture was purged with argon for 5 minutes, then 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II) (0.4 g) was added. The mixture was stirred at 100 ℃ overnight. After cooling to room temperature, the mixture is diluted with ethyl acetate and NH ₄ Aqueous Cl and brine washed and dried (MgSO) ₄ ). The solvent was evaporated and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate) to give the title compound. Mass spectrometry (ESI) ⁺ )：m/z＝243[M-OH] ⁺ 。

Step 2: (S) -4- [2,6-dimethyl-4- (2-methyl-2H-tetrazol-5-yl) -phenyl]-indan-1-ol

Dicyclohexyl- (2 ',6' -dimethyloxy-biphenyl-2-yl) -phosphine (SPhos, 30 mg) and K at room temperature ₃ PO ₄ (2M in water, 0.8 mL) was added with a stirrer, (S) -4- (4,4,5,5-tetramethyl- [1,3,2)]Dioxaborolan-2-yl) -indan-1-ol (0.10 g), 5- (4-bromo-3,5-dimethyl-phenyl) -2-methyl-2H-tetrazole (0.12 g; for its preparation see WO 2013/144097) and toluene (2 mL) in flasks. The mixture was purged with argon for 5 minutes, then palladium (II) acetate (8 mg) was added. The mixture was stirred at 100 ℃ for 1 hour. After cooling to room temperature, theThe mixture was diluted with ether and NH ₄ Washed with aqueous Cl solution and dried (MgSO) ₄ ). The solvent was evaporated and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate) to give the title compound. Mass spectrum (ESI) ⁺ )：m/z＝321[M+H] ⁺ 。

Step 3:2- { (R) -4- [2,6-dimethyl-4- (2-methyl-2H-tetrazol-5-yl) -phenyl]-indan-1-yl } -isoindole-1,3-dione

Di-tert-butyl azodicarboxylate (0.70 g) was added to (S) -4- [2,6-dimethyl-4- (2-methyl-2H-tetrazol-5-yl) -phenyl with stirrer cooled in an ice bath]-indan-1-ol (0.72 g), phthalimide (0.37 g), tri-n-butyl-phosphine (0.67 g) and tetrahydrofuran (10 mL). The ice bath was removed and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and NaHCO ₃ The aqueous solution was washed and dried (MgSO ₄ ). The solvent was evaporated and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate) to give the title compound. Mass spectrum (ESI) ⁺ )：m/z＝450[M+H] ⁺ 。

Step 4: (R) -4- [2,6-dimethyl-4- (2-methyl-2H-tetrazol-5-yl) -phenyl]Indan-1-ylamine

Hydrazine hydrate (0.83 g) was added to 2- { (R) -4- [2,6-dimethyl-4- (2-methyl-2H-tetrazol-5-yl) -phenyl with stirrer at room temperature]-indan-1-yl } -isoindole-1,3-dione (0.81 g) and methanol (5 mL). The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and filtered. The solvent was evaporated and the residue was purified by HPLC (acetonitrile/water/ammonia) to give the title compound. Mass spectrometry (ESI) ⁺ )：m/z＝303[M-NH ₂ ] ⁺ 。

Intermediate 7

4- [4- ((R) -1-amino-indan-4-yl) -3,5-dimethyl-phenoxy]-2-methyl-butan-2-ol

Step 1: (S) -4- [4- (3-hydroxy-3-methyl-butyloxy) -2,6-dimethyl-phenyl]-indan-1-ol

The title compound was prepared from (S) -4-bromo-indan-1-ol (for its preparation, see WO 2013/144098) and 4- (3-hydroxy-3-methyl-butyloxy) -2,6-dimethyl-phenylboronic acid (for its preparation, see WO 2015/44073) following a procedure similar to that described in step 2 of intermediate 6. Mass spectrometry (ESI) ⁺ )： m/z＝323[M-NH ₂ ] ⁺ 。

Step 2:2- { (R) -4- [4- (3-hydroxy-3-methyl-butyloxy) -2,6-dimethyl-phenyl]-indan-1-yl } -isoindole-1,3-dione

Following a procedure analogous to that described for intermediate 6, step 3, was performed starting from (S) -4- [4- (3-hydroxy-3-methyl-butyloxy) -2,6-dimethyl-phenyl]Indan-1-ol and phthalimide the title compound was prepared. Mass spectrometry (ESI) ⁺ )：m/z＝452[M-NH ₂ ] ⁺ 。

Step 3:4- [4- ((R) -1-amino-indan-4-yl) -3,5-dimethyl-phenoxy]-2-methyl-butan-2-ol

Following a procedure analogous to that described in step 4 of intermediate 6, starting from 2- { (R) -4- [4- (3-hydroxy-3-methyl-butyloxy) -2,6-dimethyl-phenyl]-indan-1-yl } -isoindole-1,3-dione. Mass spectrometry (ESI) ⁺ )：m/z＝323[M-NH ₂ ] ⁺ 。

Intermediate 8

(R) -4- [2,6-dimethyl-4- (2-methyl-2H-tetrazol-5-yl) -phenyl]-7-fluoro-indan-1-ylamine

Step 1: (S) -4- [2,6-dimethyl-4- (2-methyl-2H-tetrazol-5-yl) -phenyl]-7-fluoro-indan-1-ol

Following a procedure similar to that described for intermediate 6, step 2, was prepared from (S) -4- (4,4,5,5-tetramethyl- [1,3,2]Dioxaborolan-2-yl) -7-fluoroThe title compound was prepared from (S) -4-bromo-7-fluoro-indan-1-ol (obtained by the procedure described in step 1 using intermediate 6) and 5- (4-bromo-3,5-dimethyl-phenyl) -2-methyl-2H-tetrazole. Mass spectrometry (ESI) ⁺ )：m/z＝339[M+H] ⁺ 。

Step 2:5- [4- ((R) -1-azido-7-fluoro-indan-4-yl) -3,5-dimethyl-phenyl]-2-methyl-2H-tetrazole

Diphenylphosphoryl azide (2.3 mL) was added over 2 hours to (S) -4- [2,6-dimethyl-4- (2-methyl-2H-tetrazol-5-yl) -phenyl, cooled in an ice bath, equipped with a stirrer]-7-fluoro-indan-1-ol (3.45 g), 1.8-diazabicyclo [5.4.0]Undec-7-ene (2.35 mL) and toluene (75 mL). The ice bath was removed and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with water and brine and dried (Na) ₂ SO ₄ ). The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 9:1 → 3:2) to give the title compound. Mass spectrometry (ESI) ⁺ )： m/z＝364[M+H] ⁺ 。

Step 3: (R) -4- [2,6-dimethyl-4- (2-methyl-2H-tetrazol-5-yl) -phenyl]-7-fluoro-indan-1-ylamine

At room temperature, will be charged with 5- [4- ((R) -1-azido-7-fluoro-indan-4-yl) -3,5-dimethyl-phenyl]A flask of-2-methyl-2H-tetrazole (2.33 g), 10% palladium on carbon (0.4 g) and ethanol (75 mL) was shaken under an atmosphere of hydrogen (3 bar) for 7 hours. The mixture was filtered and the filtrate was concentrated to give the title compound. Mass spectrum (ESI) ⁺ )：m/z＝338[M+H] ⁺ 。

Intermediate 9

4- [4- ((R) -1-amino-7-fluoro-indan-4-yl) -3,5-dimethyl-phenoxy]-2-methyl-butan-2-ol

Step 1: (S) -7-fluoro-4- [4- (3-hydroxy-3-methyl-butyloxy) -2,6-dimethyl-phenyl]-indan-1-alcohols

The title compound was prepared from (S) -4-bromo-7-fluoro-indan-1-ol (for its preparation, see WO 2013/144097) and 4- (3-hydroxy-3-methyl-butyloxy) -2,6-dimethyl-phenylboronic acid (for its preparation, see WO 2015/44073) following a procedure similar to that described in step 2 of intermediate 6. Mass spectrometry (ESI) ⁺ )：m/z＝341[M-OH] ⁺ 。

Step 2:4- [4- ((R) -1-azido-7-fluoro-indan-4-yl) -3,5-dimethyl-phenoxy]-2-methyl-butan-2-ol

Following a procedure analogous to that described for intermediate 8, step 2, was performed from (S) -7-fluoro-4- [4- (3-hydroxy-3-methyl-butyloxy) -2,6-dimethyl-phenyl]Indan-1-ol the title compound is prepared. Mass spectrometry (ESI) ⁺ )： m/z＝406[M+Na] ⁺ 。

Step 3:4- [4- ((R) -1-amino-7-fluoro-indan-4-yl) -3,5-dimethyl-phenoxy]-2-methyl-butan-2-ol

Following a procedure analogous to that described for intermediate 8, step 3, was performed starting from 4- [4- ((R) -1-azido-7-fluoro-indan-4-yl) -3,5-dimethyl-phenoxy]-2-methyl-butan-2-ol the title compound was prepared. Mass spectrometry (ESI) ⁺ )：m/z＝341[M-NH ₂ ] ⁺ 。

Intermediate 10

(R) -7-fluoro-4-trimethylsilyl-indan-1-ylamine

Step 1: (S) -7-fluoro-4-trimethylsilyl-indan-1-ol

To a flask cooled to-75 deg.C equipped with a stirrer, (S) -4-bromo-7-fluoro-indan-1-ol (10.0 g) and tetrahydrofuran (80 mL) was added n-butyllithium (1.6 mol/L in hexane; 60 mL) dropwise. The mixture was stirred at-70 ℃ below for 45 minutes, then chlorotrimethylsilane (12 mL) was added. The mixture was allowed to warm to room temperature overnight. The mixture was cooled to-50 ℃, treated with 4M aqueous HCl (25 mL), and heated toAnd (4) room temperature. The mixture was concentrated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 3:1 → 2:3) to give the title compound. Mass spectrometry (ESI) ⁺ )：m/z＝207[M-OH] ⁺ 。

Step 2: ((R) -1-azido-7-fluoro-indan-4-yl) -trimethyl-silane

The title compound was prepared from (S) -7-fluoro-4-trimethylsilyl-indan-1-ol following a procedure analogous to that described for intermediate 8, step 2. Mass spectrometry (ESI) ⁺ )：m/z＝207[M-N ₃ ] ⁺ 。

Step 3: (R) -7-fluoro-4-trimethylsilyl-indan-1-ylamine

The title compound was prepared from ((R) -1-azido-7-fluoro-indan-4-yl) -trimethyl-silane following a procedure analogous to that described for intermediate 8, step 3. Mass spectrometry (ESI) ⁺ )：m/z＝224[M+H] ⁺ 。

Intermediate 11

(1S, 2S) -2- {5- [ (R) -7-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2]Dioxaborolane-2- -indan-1-ylamino]-pyrazin-2-yl } -cyclopropanecarboxylic acid methyl ester

Step 1: (1S, 2S) -2- [5- ((R) -7-fluoro-4-trimethylsilyl-indan-1-ylamino) -pyrazin-2-yl]-cyclopropanecarboxylic acid

A vial containing stir bar, (R) -7-fluoro-4-trimethylsilyl-indan-1-ylamine (4.35 g), (1S, 2S) -2- (5-chloro-pyrazin-2-yl) -cyclopropanecarboxylic acid (3.58 g), and 2-methyl-2-butanol (50 mL) was purged with argon for 10 minutes. Chloro [2- (dicyclohexylphosphino) -3,6-dimethyloxy-2 ',4',6 '-triisopropyl-1,1' -biphenyl was added][2- (2-aminoethyl) phenyl group]Palladium (II) (BRETTPHOS Pd G1 methyl tert-butyl ether adduct; 0.58G) and sodium tert-amylate (7.78G), and the mixture was stirred at 85 ℃ for 2 hours. After cooling to room temperature, acetic acid (3.9 mL) and THF were added and the mixture was stirred vigorously. The mixing is carried outThe material was diluted with water and ethyl acetate and filtered over celite. The organic phase of the filtrate was separated, washed with brine and dried (MgSO) ₄ ). The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate) to give the title compound. Mass spectrum (ESI) ⁺ )：m/z＝386[M+H] ⁺ 。

Step 2: (1S, 2S) -2- [5- ((R) -7-fluoro-4-trimethylsilyl-indan-1-ylamino) -pyrazin-2-yl]-cyclopropanecarboxylic acid methyl ester

Iodomethane (1.3 mL) was added to (1S, 2S) -2- [5- ((R) -7-fluoro-4-trimethylsilyl-indan-1-ylamino) -pyrazin-2-yl at room temperature]Cyclopentanecarboxylic acid (6.43 g), K ₂ CO ₃ (2.65 g) and N, N-dimethylformamide (30 mL). The mixture was stirred at room temperature for 6 hours. The mixture was concentrated and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate 4:1 → 1:1) to give the title compound. Mass spectrometry (ESI) ⁺ )：m/z＝400[M+H] ⁺ 。

Step 3: (1S, 2S) -2- [5- ((R) -7-fluoro-4-iodo-indan-1-ylamino) -pyrazin-2-yl]-cyclopropanecarboxylic acid methyl ester

Iodine monochloride (1 mol/L in dichloromethane; 15 mL) was added to (1S, 2S) -2- [5- ((R) -7-fluoro-4-trimethylsilyl-indan-1-ylamino) -pyrazin-2-yl) cooled in an ice bath over 1 hour]-methyl cyclopropanecarboxylate (3.00 g) in dichloromethane (20 mL). The solution was stirred in a cold bath for 1 hour. 1,3,5-trimethyloxybenzene (1.89 g) was added and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane and saturated NaHCO ₃ And (4) washing with an aqueous solution. The solvent was evaporated and the residue was chromatographed on silica gel (petroleum ether/ethyl acetate/methanol 4. Mass spectrometry (ESI) ⁺ )：m/z＝454[M+H] ⁺ 。

Step 4: (1S, 2S) -2- {5- [ (R) -7-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2]Dioxaborolan-2-yl) -indan-1-ylamino]-pyrazin-2-yl } -cyclopropanecarboxylic acid methyl ester

According to a method analogous to that of intermediate 6The procedure described in step 1, the title compound consisting of (1S, 2S) -2- [5- ((R) -7-fluoro-4-iodo-indan-1-ylamino) -pyrazin-2-yl]-methyl cyclopropanecarboxylate preparation; using Pd (PPh) ₃ ) ₄ And dimethyl sulfoxide instead of PdCl ₂ (dppf) and 1,4-bis

An alkane. Mass spectrum (ESI +): m/z =454[ M + H ]] ⁺ 。

Intermediate 12

((R) -4-bromo-7-fluoro-indan-1-yl) -carbamic acid tert-butyl ester

Step 1:2- ((R) -4-bromo-7-fluoro-indan-1-yl) -isoindole-1,3-dione

The title compound was prepared from (S) -4-bromo-7-fluoro-indan-1-ol and phthalimide following a procedure analogous to that described in step 3 for intermediate 6. Mass spectrometry (ESI) ⁺ )：m/z＝360/362(Br) [M+H] ⁺ 。

Step 2: (R) -4-bromo-7-fluoro-indan-1-ylamine

The title compound was prepared from 2- ((R) -4-bromo-7-fluoro-indan-1-yl) -isoindole-1,3-dione following an analogous procedure as described in step 4 for intermediate 6; this compound can be converted to its hydrochloride salt by treatment with a solution of HCl (5 mol/L in isopropanol) in ethyl acetate. Mass spectrometry (ESI) ⁺ )： m/z＝230/232(Br)[M+H] ⁺ 。

Step 3: ((R) -4-bromo-7-fluoro-indan-1-yl) -carbamic acid tert-butyl ester

Triethylamine (9.3 mL) and di-tert-butylbicarbonate (7.12 g) were added to the hydrochloride salt of (R) -4-bromo-7-fluoro-indan-1-ylamine (8.70 g) in tetrahydrofuran (100 mL) at room temperature. The solution was stirred at room temperature overnight. Water was added and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried (MgSO) ₄ ) And concentrated to give the title compound. Mass spectrum (ESI) ⁺ ): m/z =273/275 (Br) [ M-tert-butyl group] ⁺ 。

Step 4: [ (R) -7-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2]Dioxaborolan-2-yl) -indan-1-yl]-carbamic acid tert-butyl ester

The title compound was prepared from ((R) -4-bromo-7-fluoro-indan-1-yl) -carbamic acid tert-butyl ester following a procedure similar to that described in step 1 for intermediate 6. Mass spectrometry (ESI) ⁺ ): m/z =322[ M-tert-butyl ]] ⁺ 。

Intermediate 13

(3R, 4R) -4- [4- ((R) -1-amino-7-fluoro-indan-4-yl) -3,5-dimethyl-phenoxy]-tetrahydro-furan Pyran-3-ols

Step 1: [ (3R, 4R) -4- (4-bromo-3,5-dimethyl-phenoxy) -tetrahydrofuran-3-yloxy]-tert-butyl-dimethyl-silane

CuI (0.12 g) and 1,10-phenanthroline (0.23 g) were added to 2-bromo-5-iodo-m-xylene (2.00 g), (3R, 4R) -4- (tert-butyl-dimethyl-silanyloxy) -tetrahydrofuran-3-ol (1.72 g), cs, with stirring, at room temperature ₂ CO ₃ (4.11 g) and toluene (10 mL). The mixture was stirred at 115 ℃ overnight. After cooling to room temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with 1M aqueous HCl and dried (MgSO) ₄ ). The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 49. Mass spectrometry (ESI) ⁺ )：m/z＝401/403(Br)[M+H] ⁺ 。

Step 2: ((R) -4- {4- [ (3R, 4R) -4- (tert-butyl-dimethyl-silanyloxy) -tetrahydro-furan-3-yloxy)]-2,6-dimethyl-phenyl } -7-fluoro-indan-1-yl) -carbamic acid tert-butyl ester

Argon was used to purge [ (3R, 4R) -4- (4-bromo-3,5-dimethyl-phenoxy) equipped with stirrerYl) -tetrahydro-furan-3-yloxy]-tert-butyl-dimethyl-silane (0.80 g), [ (R) -7-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2]Dioxaborolan-2-yl) -indan-1-yl]-carbamic acid tert-butyl ester (0.64 g), K ₃ PO ₄ (0.96 g), water (4.3 mL) and 1,4-bis

Vial of alkane (13 mL) for 10 min. Bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (PdCl) was added ₂ (Amphos) ₂ (ii) a 0.10 g), and the mixture was stirred at 80 ℃ for 1 hour. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The combined extracts were dried (MgSO) ₄ ) And concentrated to give the crude product, which was used as such in the next step. Mass spectrometry (ESI) ⁺ )： m/z＝516[M+H] ⁺ 。

Step 3: (3R, 4R) -4- [4- ((R) -1-amino-7-fluoro-indan-4-yl) -3,5-dimethyl-phenoxy]-tetrahydro-furan-3-ol

HCl solution (4 mol/L at 1,4-bis) was added at room temperature

To the alkyl, 10 mL) was added ((R) -4- {4- [ (3R, 4R) -4- (tert-butyl-dimethyl-silanyloxy) -tetrahydro-furan-3-yloxy)]1,4-Di of-2,6-dimethyl-phenyl } -7-fluoro-indan-1-yl) -carbamic acid tert-butyl ester (1.56 g)

Alkane (5 mL) solution. The solution was stirred at room temperature for 1 hour and then concentrated. Purification of the residue by HPLC (acetonitrile/water/trifluoroacetic acid) gave the title compound. Mass spectrometry (ESI) ⁺ )：m/z＝341[M-NH ₂ ] ⁺ 。

Intermediate 14

(R) -7-fluoro-4- [4- (3-methanesulfonyl-propyloxy) -2,6-dimethyl-phenyl]Indan-1-ylamine

Step 1: { (R) -7-fluoro-4- [4- (3-methanesulfonyl-propyloxy) -2,6-dimethyl-phenyl]-indan-1-yl } -carbamic acid tert-butyl ester

Following a procedure similar to that described in step 2 of intermediate 13, from 2-bromo-5- (3-methanesulfonyl-propyloxy) -1,3-dimethyl-benzene (for its preparation, see WO 2013/178575) and [ (R) -7-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2)]Dioxaborolan-2-yl) -indan-1-yl]Tert-butyl carbamate the title compound is prepared. Mass spectrometry (ESI) ⁺ ): m/z =436[ 2] M-tert-butyl group] ⁺ 。

Step 2: (R) -7-fluoro-4- [4- (3-methanesulfonyl-propyloxy) -2,6-dimethyl-phenyl]Indan-1-ylamine

Following a procedure analogous to that described for intermediate 13, step 3, from { (R) -7-fluoro-4- [4- (3-methanesulfonyl-propyloxy) -2,6-dimethyl-phenyl]-indan-1-yl } -carbamic acid tert-butyl ester the title compound is prepared. Mass spectrometry (ESI) ⁺ )：m/z＝375[M-NH ₂ ] ⁺ 。

Intermediate 15

2- ((R) -4-bromo-indan-1-yl) -isoindole-1,3-dione

The title compound was prepared from (S) -4-bromo-indan-1-ol following a procedure analogous to that described for intermediate 6, step 3. Mass spectrometry (ESI) ⁺ )：m/z＝342/344(Br)[M+H] ⁺ 。

Intermediate 16

(R) -4- (3-fluoro-4-methyloxy-phenyl) -indan-1-ylamine

Step 1:2- [ (R) -4- (3-fluoro-4-methyl) methyl esterOxy-phenyl) -indan-1-yl]-isoindole-1,3-dione

Argon purge with stirrer, 2- ((R) -4-bromo-indan-1-yl) -isoindole-1,3-dione (0.50 g), 3-fluoro-4-methyloxy-phenylboronic acid (0.28 g), dicyclohexyl- (2 ',6' -dimethyloxy-biphenyl-2-yl) -phosphine (30 mg), K ₃ PO ₄ Vials of (2 mol/L in water, 4.5 mL) and toluene (10 mL) for 10 minutes. Pd (OAc) is added ₂ (8 mg) and the mixture was stirred at 110 ℃ for 30 minutes. After cooling to room temperature, the mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. With 1M H ₃ PO ₄ The combined extracts were washed with aqueous solution and brine, dried (MgSO) ₄ ) And concentrated to give the crude product, which was used as such in the next step. Mass spectrum (ESI) ⁺ )：m/z＝388[M+H] ⁺ 。

Step 2: (R) -4- (3-fluoro-4-methyloxy-phenyl) -indan-1-ylamine

Following a procedure analogous to that described in step 4 of intermediate 6, from 2- [ (R) -4- (3-fluoro-4-methyloxy-phenyl) -indan-1-yl]-isoindole-1,3-dione. Mass spectrum (ESI) ⁺ )： m/z＝241[M-NH ₂ ] ⁺ 。

Intermediate 17

(R) -4- [4- (5-Methyloxy-pyrazin-2-yl) -phenyl]Indan-1-ylamine

Step 1:2- { (R) -4- [4- (5-Methyloxy-pyrazin-2-yl) -phenyl]-indan-1-yl } -isoindole-1,3-dione

The title compound was prepared from 2- ((R) -4-bromo-indan-1-yl) -isoindole-1,3-dione and 4- (5-methyloxy-pyrazin-2-yl) -phenylboronic acid following an analogous procedure as described in step 1 for intermediate 16. Mass spectrometry (ESI) ⁺ )：m/z＝448[M+H] ⁺ 。

Step 2: (R) -4- [4- (5-Methyloxy-pyrazin-2-yl) -phenyl]Indan-1-ylamine

Following a procedure analogous to that described in step 4 of intermediate 6, starting from 2- { (R) -4- [4- (5-methyloxy-pyrazin-2-yl) -phenyl]-indan-1-yl } -isoindole-1,3-dione. Mass spectrometry (ESI) ⁺ )：m/z＝301[M-NH ₂ ] ⁺ 。

Example 1

Trans-2- (5- { (R) -7-fluoro-4- [4- (3-hydroxy-3-methyl-butyloxy) -2,6-dimethyl-phenyl]-indene Hen-1-ylamino } -pyrazin-2-yl) -cyclopropanecarboxylic acid (a mixture of about 1:1 as the trans diastereomer relative to cyclopropane Compound)

Argon purge with stirrer, sodium tert-butoxide (41 mg), 4- [4- ((R) -1-amino-7-fluoro-indan-4-yl) -3,5-dimethyl-phenoxy]-2-methyl-butan-2-ol (61 mg), trans-2- (5-bromo-pyrazin-2-yl) -cyclopropanecarboxylic acid ethyl ester (45 mg) and 1,4-bis

Vial of alkane (3 mL) for 5 minutes. Adding chloro [2- (dicyclohexylphosphino) -3,6-dimethyl-oxy-2 ',4',6 '-triisopropyl-1,1' -biphenyl][2- (2-aminoethyl) phenyl group]Palladium (II) (BRETTPHOS Pd G1 methyl tert-butyl ether adduct; 7 mg) and the mixture was stirred at 100 ℃ for 1 hour. After cooling to room temperature, aqueous KOH (4 mol/L,2 mL) was added and the mixture was stirred at room temperature for 2 hours. 4M aqueous HCl was added and the acidified mixture was extracted with ethyl acetate. The extract was concentrated and chromatographed (HPLC; acetonitrile, water and trifluoroacetic acid as eluent) to give the title compound. LC (method 1): t is t _R =1.07min; mass spectrometry (ESI) ⁺ )：m/z＝520[M+H] ⁺ 。

Example 2

(1S, 2S) -2- (5- { (R) -7-fluoro-4- [4- (3-hydroxy-3-methyl-butyloxy) -2,6-dimethyl-benzene Base of]Indan-1-ylamino } -pyrazine-2-yl) -cyclopropanecarboxylic acids

Argon purge equipped with a stirrer, 4- [4- ((R) -1-amino-7-fluoro-indan-4-yl) -3,5-dimethyl-phenoxy]-2-methyl-butan-2-ol (0.18 g), (1S, 2S) -2- (5-bromo-pyrazin-2-yl) -cyclopropanecarboxylic acid (0.14 g), [ (2,6-dimethylphenyl) carbamoyl]Formic acid (19 mg), K ₃ PO ₄ (0.21 g) and dimethylsulfoxide (0.5 mL) for 10 minutes. CuI (9 mg) was added and the mixture was stirred at 100 ℃ for 18 hours. After cooling to room temperature, 4M aqueous NaOH (3 mL) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted once with ethyl acetate. The aqueous phase was acidified (pH) with 4M aqueous HCl<4) And extracted with ethyl acetate. The combined extracts were concentrated and the residue was chromatographed (HPLC; water, acetonitrile and ammonia as eluent) to give the title compound. LC (method 1): t is t _R =1.06min; mass spectrometry (ESI) ⁺ )：m/z＝520[M+H] ⁺ 。

Alternatively, the title compound may be obtained as follows:

to a stirred tank of 4- [4- ((R) -1-amino-7-fluoro-indan-4-yl) -3,5-dimethyl-phenoxy]Vials of-2-methyl-butan-2-ol (0.80 g), (1s, 2s) -2- (5-chloro-pyrazin-2-yl) -cyclopropanecarboxylic acid (0.55 g) and 2-methyl-2-butanol (20 mL) were purged with argon for 10 minutes. Adding chloro [2- (dicyclohexylphosphino) -3,6-dimethyl-oxy-2 ',4',6 '-triisopropyl-1,1' -biphenyl][2- (2-aminoethyl) phenyl group]Palladium (II) (BRETTPHOS Pd G1 methyl tert-butyl ether adduct; 60 mg) and sodium tert-amylate (1.40G), and the mixture was stirred at 100 ℃ for 45 minutes. After cooling to room temperature, acetic acid (0.6 mL) was added and the mixture was stirred vigorously. Water was added and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine and dried (MgSO) ₄ ) And concentrated. The residue was chromatographed on silica gel (dichloromethane/methanol) to give the title compound.

Example 3

(1R, 2R) -2- (5- { (R) -7-fluoro-4- [4- (3-hydroxy-3-methyl-butyloxy) -2,6-dimethyl-benzene Base of]-indan-1-ylamino } -pyrazin-2-yl) -cyclopropanecarboxylic acid

Following an analogous procedure to that described in example 2 (which used CuI), starting from 4- [4- ((R) -1-amino-7-fluoro-indan-4-yl) -3,5-dimethyl-phenoxy]-2-methyl-butan-2-ol and (1r, 2r) -2- (5-bromo-pyrazin-2-yl) -cyclopropanecarboxylic acid the title compound was prepared. LC (method 1): t is t _R =1.07min; mass spectrometry (ESI) ^- )： m/z＝518[M-H] ^- 。

Example 4

(1S, 2S) -2- (5- { (R) -7-fluoro-4- [4- (3-methanesulfonyl-propyloxy) -2,6-dimethyl-phenyl]-indene Hen-1-ylamino } -pyrazin-2-yl) -cyclopropanecarboxylic acid

Following an analogous procedure to that described in example 2, which used CuI, from (R) -7-fluoro-4- [4- (3-methanesulfonyl-propyloxy) -2,6-dimethyl-phenyl]-indan-1-ylamine and (1S, 2S) -2- (5-bromo-pyrazin-2-yl) -cyclopropanecarboxylic acid the title compound was prepared. LC (method 1): t is t _R =1.00min; mass spectrometry (ESI) ⁺ )： m/z＝554[M+H] ⁺ 。

Example 5

(1R, 2R) -2- (5- { (R) -7-fluoro-4- [4- (3-methanesulfonyl-propyloxy) -2,6-dimethyl-phenyl]-indene Hen-1-ylamino } -pyrazin-2-yl) -cyclopropanecarboxylic acid

According to the analogy ofThe procedure described in example 2 (which used CuI) the title compound was prepared from (R) -7-fluoro-4- [4- (3-methanesulfonyl-propyloxy) -2,6-dimethyl-phenyl]-indan-1-ylamine and (1R, 2R) -2- (5-bromo-pyrazin-2-yl) -cyclopropanecarboxylic acid. LC (method 1): t is t _R =1.00min; mass spectrometry (ESI) ⁺ )：m/z＝554[M+H] ⁺ 。

Example 6

(1S, 2S) -2- (5- { (R) -4- [2,6-dimethyl-4- (2-methyl-2H-tetrazol-5-yl) -phenyl]Indan-1-carboxylic acid derivatives Aminoyl-pyrazin-2-yl-cyclopropanecarboxylic acids

To the solution is added a stirrer, (R) -4- [2,6-dimethyl-4- (2-methyl-2H-tetrazol-5-yl) -phenyl]-indan-1-ylamine (75 mg), (1s, 2s) -2- (5-chloro-pyrazin-2-yl) -cyclopropanecarboxylic acid (78% ee 50mg) and 1,4-bis

A vial of alkane (2 mL) was purged with argon for 10 minutes. Adding chloro [2- (dicyclohexylphosphino) -3,6-dimethyl-oxy-2 ',4',6 '-triisopropyl-1,1' -biphenyl][2- (2-aminoethyl) phenyl group]Palladium (II) (BRETTPHOS Pd G1 methyl tert-butyl ether adduct; 9 mg), 2- (dicyclohexylphosphino) -3,6-dimethyloxy-2 ',4',6 '-triisopropyl-1,1' -biphenyl (6 mg) and sodium tert-butoxide (0.10G), the mixture was stirred at 85 ℃ for 90 minutes. After cooling to room temperature, acetic acid (60 μ L) and THF were added and the mixture was stirred vigorously. The mixture was filtered through celite and the filtrate was chromatographed (HPLC; water/acetonitrile/trifluoroacetic acid) to give the title compound. LC (method 1): t is t _R =1.05min; mass spectrum (ESI) ⁺ )：m/z＝482[M+H] ⁺ 。

Example 7

(1S, 2S) -2- (5- { (R) -4- [4- (3-hydroxy-3-methyl-butyloxy) -2,6-dimethyl-phenyl]-indene Hen-1-ylamino } -pyrazin-2-yl) -cyclopropanecarboxylic acid

Following a procedure analogous to that described in example 6, from (1S, 2S) -2- (5-chloro-pyrazin-2-yl) -cyclopropanecarboxylic acid (78% ee) and 4- [4- ((R) -1-amino-indan-4-yl) -3,5-dimethyl-phenoxy]-2-methyl-butan-2-ol the title compound was prepared. LC (method 1): t is t _R =1.06min; mass spectrometry (ESI) ⁺ )：m/z＝502[M+H] ⁺ 。

Example 8

(1S, 2S) -2- {5- [ (R) -4- (3-fluoro-4-methyloxy-phenyl) -indan-1-ylamino]-pyrazin-2-yl- Cyclopropane carboxylic acids

Argon was purged to a vial containing stir bar, (R) -4- (3-fluoro-4-methyloxy-phenyl) -indan-1-ylamine (0.17 g), (1s, 2s) -2- (5-chloro-pyrazin-2-yl) -cyclopropanecarboxylic acid (78% ee 0.10g) and 2-methyl-2-butanol (6 mL) for 10 minutes. Adding chloro [2- (dicyclohexylphosphino) -3,6-dimethyl-oxy-2 ',4',6 '-triisopropyl-1,1' -biphenyl][2- (2-aminoethyl) phenyl group]Palladium (II) (BRETTPHOS Pd G1 methyl tert-butyl ether adduct; 25 mg) and sodium tert-amylate (0.30G), and the mixture was stirred at 85 ℃ for 90 minutes. After cooling to room temperature, acetic acid (0.15 mL) and THF were added and the mixture was stirred vigorously. The mixture was filtered through celite and the filtrate was chromatographed (HPLC; water/acetonitrile/trifluoroacetic acid) to give the title compound. LC (method 1): t is t _R =1.04min; mass spectrometry (ESI) ⁺ )：m/z＝420[M+H] ⁺ 。

Example 9

(1S, 2S) -2- (5- { (R) -4- [4- (5-Methyloxy-pyrazin-2-yl) -phenyl]-indan-1-ylamino } -pyridine Oxazin-2-yl-cyclopropanecarboxylic acids

According to a process similar to that described in example 6, from (1S, 2S) -2- (5-chloro-pyrazin-2-yl) -cyclopropanecarboxylic acid (78% ee) and (R) -4- [4- (5-methyloxy-pyrazin-2-yl) -phenyl]Indan-1-ylamine the title compound is prepared. LC (method 1): t is t _R =1.10min; mass spectrum (ESI) ⁺ )：m/z＝480[M+H] ⁺ 。

Following the main procedures described in step 2 of intermediate 6, step 2 of intermediate 13 and step 1 of intermediate 16, the following compounds compiled in the table below can be prepared from (1S, 2S) -2- {5- [ (R) -7-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -indan-1-ylamino ] -pyrazin-2-yl } -cyclopropanecarboxylic acid methyl ester (or its corresponding boronic acid) and the respective bromide (or chloride or iodide) of the coupling ligand via simultaneous or subsequent hydrolysis of the ester group.

A typical procedure for synthesizing this compound is shown in the following table:

to a reactor equipped with a stirrer, (1S, 2S) -2- {5- [ (R) -7-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2)]Dioxaborolan-2-yl) -indan-1-ylamino]-pyrazin-2-yl } -cyclopropanecarboxylic acid methyl ester (0.11mmol, 1 equivalent), coupling ligands such as bromide, chloride or iodide (0.17mmol, 1.5 equivalents), K ₃ PO ₄ (0.28 mmol in 0.14mL of water, 2.5 equiv.) and 1,4-bis

A vial of alkane (1.5 mL) was purged with argon for 10 minutes. Bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (PdCl) was added ₂ (Amphos) ₂ 1-5mol%; alternatively, pd-PEPSI-IHeptCl was used as a catalyst) and shaken at 80 ℃ for 2 to 16 hours. After cooling to room temperature, methanol (1.5 mL) and NaOH solution (4 mol/L in water, 0.5mL,18 equiv) were added and the mixture was shaken overnight at room temperature. The mixture was neutralized with 50% trifluoroacetic acid and chromatographed (HPLC; acetonitrile/water/ammonium hydroxide) to give the ammonium salt of the title compound, which was optionally converted to its free acid form by standard methods.

The examples in the following table are obtained from an diastereomeric mixture of (1S, 2S) -2- {5- [ (R) -7-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -indan-1-ylamino ] -pyrazin-2-yl } -cyclopropanecarboxylic acid methyl ester and about 73 of (1R, 2R) -2- {5- [ (R) -7-fluoro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -indan-1-ylamino ] -pyrazin-2-yl } -cyclopropanecarboxylic acid methyl ester, the former diastereoisomer being the most dominant. The minor diastereoisomers after coupling are usually not separated by chromatography and the product mixture obtained has a diastereoisomeric ratio comparable to that of one of the starting materials.

Claims

1. A compound having one of the following structures:

or a pharmaceutically acceptable salt thereof.

2. Formula (II)

Or a pharmaceutically acceptable salt thereof.

3. Formula (II)

Or a pharmaceutically acceptable salt thereof.

4. Is of the formula

Or a pharmaceutically acceptable salt thereof.

5. Formula (II)

Or a pharmaceutically acceptable salt thereof.

6. A pharmaceutically acceptable salt of a compound according to any one of claims 1 to 5.

7. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 5 or one or more pharmaceutically acceptable salts thereof, and optionally one or more inert carriers and/or diluents.

8. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention and/or treatment of metabolic diseases and conditions associated with such diseases.

9. The use according to claim 8, wherein the metabolic disease or condition associated with the disease is diabetes, insulin resistance, obesity, cardiovascular disease or dyslipidemia.

10. The use according to claim 8, wherein the metabolic disease is type 2 diabetes.

11. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for use as a medicament.

12. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents, optionally together with one or more inert carriers and/or diluents.

13. Pharmaceutical composition according to claim 12, wherein the further therapeutic agent is selected from the group consisting of anti-diabetic agents, agents for the treatment of overweight and/or obesity and agents for the treatment of hypertension, heart failure and/or atherosclerosis.